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The adipocyte-derived hormone, leptin, plays a key role in the maintenance of energy homeostasis. Leptin binds to the long form of its receptor, which is predominantly expressed in various hypothalamic regions, including the lateral hypothalamic area (LH) and supraoptic nucleus (SO). Several studies have suggested that leptin directly activates neuronal nitric oxide synthase, leading to increased nitric oxide production. We used histochemistry for nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) as a marker for nitric oxide synthase activity and assessed the effect of leptin on nitrergic neurons in the LH and SO of rats. We found that intraperitoneal administration of leptin led to a significant increase in the number of NADPH-d-positive neurons in the LH and SO. In addition, the intensity (optical density) of NADPH-d staining in LH and SO neurons was significantly elevated in rats that received leptin compared with saline-treated rats. These findings suggest that nitrergic neurons in the LH and SO may be implicated in mediating the central effects of leptin. [ABSTRACT FROM AUTHOR]

Introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have shown neuroprotective effects in obese mice. However, whether SGLT2i can ameliorate high-fat diet (HFD)-related ovulation disorders remains unknown. The aim of this research was to investigate whether dapagliflozin improves HFD-induced ovulatory dysfunction by attenuating microglia-mediated hypothalamic inflammation. Methods: C57BL/6J female mice fed HFD were treated with dapagliflozin (1 mg/kg) for 22 weeks. Plasma insulin, leptin, luteinizing hormone (LH), estradiol (E2), and IL-1β levels were also tested. Microglial morphology, cell numbers, and SGLT2 expression were evaluated using immunofluorescence. The expression of IL-1β, NLRP3, kisspeptin, gonadotropin-releasing hormone (GnRH), SGLT2, insulin, and leptin receptors in the hypothalamus was determined using immunohistochemical staining. We also examined the effects of dapagliflozin on glucose metabolism and the release of inflammatory factor in palmitic acid (PA)-treated HMC3 cells. Results: As expected, dapagliflozin improved HFD-induced metabolic disturbances, peripheral versus central insulin and leptin resistance and also restored the regular estrous cycle. Furthermore, dapagliflozin blunted microglia activation, NLRP3 inflammasome priming, hypothalamic inflammation, and increased the expression of GnRH and kisspeptin at proestrus in the hypothalamus. Additionally, dapagliflozin markedly reduced IL-6 and NO release and fat accumulation, decreased lactic acid production and glucose consumption, and inhibited mammalian target of rapamycin (mTOR) and hexokinase 2 (HK2) expression in PA-treated HMC3 cells. These effects suggest that dapagliflozin reduced the mTOR/HK2-mediated aerobic glycolysis. Conclusions: Dapagliflozin improved HFD-related ovulation disorders by regulating glucose metabolism through mTOR/HK2 signaling and attenuating microglia-mediated hypothalamic inflammation. These results validate the novel role for the neuroprotection of SGLT2i in HFD-induced obesity and ovulation disorders. [ABSTRACT FROM AUTHOR]

The article discusses the physiological process of torpor and hibernation in endothermic animals, including mice. Torpor is a hypoactive metabolic state that animals enter during periods of low temperatures and food scarcity to conserve energy. The central nervous system, particularly the hypothalamus, plays a crucial role in regulating torpor. The article presents recent findings on the neural circuits involved in torpor regulation, specifically focusing on the antero-preoptic area, medial preoptic area, and dorsomedial hypothalamus. The article also highlights the need for further research to understand the mechanisms underlying torpor and hibernation in different animal species, including humans. [Extracted from the article]

Leptin is an adipocyte‐derived hormone that modulates food intake, energy balance, neuroendocrine status, thermogenesis, and cognition. Whereas a high density of leptin receptors has been detected in the basolateral amygdala (BLA) neurons, the physiological functions of leptin in the BLA have not been determined yet. We found that application of leptin excited BLA principal neurons by activation of the long form leptin receptor, LepRb. The LepRb‐elicited excitation of BLA neurons was mediated by depression of the G protein‐activated inwardly rectifying potassium (GIRK) channels. Janus Kinase 2 (JAK2) and phosphoinositide 3‐kinase (PI3K) were required for leptin‐induced excitation of BLA neurons and depression of GIRK channels. Microinjection of leptin into the BLA reduced food intake via activation of LepRb, JAK2, and PI3K. Our results may provide a cellular and molecular mechanism to explain the physiological roles of leptin in vivo. [ABSTRACT FROM AUTHOR]

The arcuate nucleus is a crucial hypothalamic brain region involved in regulating body weight homeostasis. Neurons within the arcuate nucleus respond to peripheral metabolic signals, such as leptin, and relay these signals via neuronal projections to brain regions both within and outside the hypothalamus, ultimately causing changes in an animal's behaviour and physiology. There is a substantial amount of evidence to indicate that leptin is intimately involved with the postnatal development of arcuate nucleus melanocortin circuitry. Further, it is clear that leptin signalling directly in the arcuate nucleus is required for circuitry development. However, as leptin receptor long isoform (Leprb) mRNA is expressed in multiple nuclei within the developing hypothalamus, including the postsynaptic target regions of arcuate melanocortin projections, this raises the possibility that leptin also signals in these nuclei to promote circuitry development. Here, we used RT‐qPCR and RNAscope® to reveal the spatio‐temporal pattern of Leprb mRNA in the early postnatal mouse hypothalamus. We found that Leprb mRNA expression increased significantly in the arcuate nucleus, ventromedial nucleus and paraventricular nucleus of the hypothalamus from P8, in concert with the leptin surge. In the dorsomedial nucleus of the hypothalamus, increases in Leprb mRNA were slightly later, increasing significantly from P12. Using duplex RNAscope®, we found Leprb co‐expressed with Sim1, Pou3f2, Mc4r and Bdnf in the paraventricular nucleus at P8. Together, these data suggest that leptin may signal in a subset of neurons postsynaptic to arcuate melanocortin neurons, as well as within the arcuate nucleus itself, to promote the formation of arcuate melanocortin circuitry during the early postnatal period. [ABSTRACT FROM AUTHOR]

Leptin (Lep) plays a crucial role in controlling food intake and maintaining energy balance in mammals. While several studies have shown the presence of multiple leptin genes in teleosts, limited information is currently available on how sex steroid hormones regulate the expression of these genes in fish. In this study, we used two previously expressed and purified leptin proteins to incubate four tissues in vitro (hypothalamic-pituitary-gonadal axis and liver) and used the RT-qPCR method to detect the expression of genes related to growth and reproduction in tongue sole (Cynoglossus semilaevis). The results showed that both recombinant LepA and LepB proteins of tongue sole almost entirely suppressed the expression of genes related to growth and reproduction in the hypothalamic-pituitary-gonadal axis and liver, while LepB may have had a positive role on steroid synthesis in gonads. Further, a high concentration of LepA facilitated the expression of IGF-Ι in liver. At the same time, we utilized human leptin to incubate four tissues in vitro; although most of them had trends similar to those stimulated with tongue sole leptins, there were still some differences, indicating differences among leptin homologs between humans and fishes. To our knowledge, this is the first study to explore the function of tongue sole LepA and LepB within the hypothalamic-pituitary-gonadal axis and liver in vitro. Our results provide a valuable resource and foundation for future studies. [ABSTRACT FROM AUTHOR]

[Display omitted] • 80% of POMC neurons of the retrochiasmatic area (RCA) express the leptin receptor. • 42% of POMC neurons of the arcuate nucleus (ARC) express the leptin receptor. • Leptin excites 14% of definitive POMCRCA and 25% of definitive POMCARC neurons. • Leptin inhibits 10% of definitive POMCRCA and 13% of definitive POMCARC neurons. • POMC neurons from females are less responsive to 100 nM of leptin than males. Pro-opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus (ARC) are considered a major site of leptin action. Due to increasing evidence that POMC neurons are highly heterogeneous and indications that the conventional molecular tools to study their functions have important limitations, a reassessment of leptin's effects on definitive POMC neurons is needed. POMC neurons are also expressed in the retrochiasmatic area (RCA), where their function is poorly understood. Furthermore, the response of POMC neurons to leptin in females is largely unknown. Therefore, the present study aimed to determine the differences in leptin responsiveness of POMC neurons in the ARC and the RCA using a mouse model allowing adult-inducible fluorescent labeling. We performed whole-cell patch clamp electrophysiology on 154 POMC neurons from male and female mice. We confirmed and extended the model by which leptin depolarizes POMC neurons, in both the ARC and the RCA. Furthermore, we characterized the electrophysiological properties of an underappreciated subpopulation representing ∼10% of hypothalamic POMC neurons that are inhibited by leptin. We also provide evidence that sex does not appear to be a major determinant of basal properties and leptin responsiveness of POMC neurons, but that females are overall less responsive to leptin compared to males. [ABSTRACT FROM AUTHOR]

Despite its important role in numerous physiological functions, including regulation of appetite and body weight, immune function and normal sexual maturation, raised leptin levels could result in significant damaging effects on sperm. The adverse effects of leptin on the male reproductive system result from its direct actions on the reproductive organs and cells instead of the hypothalamus–pituitary–gonadal axis. Binding of leptin to the receptors in the seminiferous tubular cells of the testes increases free radical production and decreases the gene expression and activity of endogenous enzymatic antioxidants. These effects are mediated via the PI3K pathway. The resultant oxidative stress causes significant damage to the seminiferous tubular cells, germ cells and sperm DNA leading to apoptosis, increased sperm DNA fragmentation, decreased sperm count, increased fraction of sperm with abnormal morphology, and decreased seminiferous tubular height and diameter. This review summarises the evidence in the literature on the adverse effects of leptin on sperm, which could underlie the often-reported sperm abnormalities in obese hyperleptinaemic infertile males. Although leptin is necessary for normal reproductive function, its raised levels could be pathologic. There is, therefore, a need to identify the cut-off level in the serum and seminal fluid above which leptin becomes pathological for better management of leptin associated adverse effects on male reproductive function. Sperm abnormalities are commonly reported in men with high leptin levels. This review examines the literature to ascertain a link between leptin and abnormal sperm parameters. Evidence suggests that leptin impacts sperm, and is probably responsible for the sperm abnormalities in men with raised leptin levels. [ABSTRACT FROM AUTHOR]

The adipokine leptin plays an important role in the regulation of the reproductive system. It stimulates the activity of the hypothalamic–pituitary–gonadal axis by indirectly affecting gonadoliberin (GnRH)-secreting neurons and modulates testicular steroidogenesis via binding to leptin receptors in Leydig cells. The leptin fragment (LF) 116–122, which includes the main receptor-binding determinants of this adipokine, normalizes metabolic parameters in animals with a diet-induced obesity. However, its ability to influence the testicular steroidogenic function, including through interaction with hypothalamic GnRH neurons, has not been studied. The aim of this work was to study the effects of a single and 3-day intranasal LF administration (200 µg/rat) on blood testosterone levels and expression of steroidogenic genes in the testes of mature male Wistar rats, as well as to evaluate the steroidogenic activity of LF upon testosterone synthesis stimulation by human chorionic gonadotropin (hCG, 15 IU/rat, s.c.) and inhibition by the GnRH receptor antagonist Cetrorelix (75 µg/kg, s.c.). It was shown that a single LF administration increases blood testosterone levels, while a 3-day administration enhances the steroidogenic effect of hCG. LF and hCG increased the expression of the Star gene that encodes the key regulatory protein of steroidogenesis StAR. Cetrorelix administration reduced blood testosterone levels and Star expression, while compensatory increasing gene expression of the luteinizing hormone receptor. The potentiating effect of LF on hCG-induced stimulation of testosterone synthesis and Star expression was not detected after Cetrorelix treatment. Thus, LF is able to stimulate testicular steroidogenesis in rats by itself and potentiate the steroidogenic effects of hCG. Since its effects are suppressed in the presence of a GnRH antagonist, there are grounds to assume that they are implemented via stimulation of hypothalamic GnRH neurons. [ABSTRACT FROM AUTHOR]

Leptin is an adipokine with a pleiotropic impact on many physiological processes, including hypothalamic-pituitary-somatotropic (HPS) axis activity, which plays a key role in regulating mammalian metabolism. Leptin insensitivity/resistance is a pathological condition in humans, but in seasonal animals, it is a physiological adaptation. Therefore, these animals represent a promising model for studying this phenomenon. This study aimed to determine the influence of leptin on the activity of the HPS axis. Two in vivo experiments performed during short- and long-day photoperiods were conducted on 12 ewes per experiment, and the ewes were divided randomly into 2 groups. The arcuate nucleus, paraventricular nucleus, anterior pituitary (AP) tissues, and blood were collected. The concentration of growth hormone (GH) was measured in the blood, and the relative expression of GHRH, SST, GHRHR, SSTR1, SSTR2, SSTR3, SSTR5, LEPR, and GH was measured in the collected brain structures. The study showed that the photoperiod, and therefore leptin sensitivity, plays an important role in regulating HPS axis activity in the seasonal ewe. However, leptin influences the release of GH in a season-dependent manner, and its effect seems to be targeted at the posttranscriptional stages of GH secretion. [ABSTRACT FROM AUTHOR]

The hormone leptin is known to robustly suppress food intake by acting upon the leptin receptor (LepR) signaling system residing within the agouti-related protein (AgRP) neurons of the hypothalamus. However, clinical studies indicate that leptin is undesirable as a therapeutic regiment for obesity, which is at least partly attributed to the poorly understood complex secondary structure and key signaling mechanism of the leptin-responsive neural circuit. Here, we show that the LepR-expressing portal neurons send GABAergic projections to a cohort of α3-GABAA receptor expressing neurons within the dorsomedial hypothalamic nucleus (DMH) for the control of leptinmediated obesity phenotype. We identified the DMH as a key brain region that contributes to the regulation of leptin-mediated feeding. Acute activation of the GABAergic AgRP-DMH circuit promoted food intake and glucose intolerance, while activation of post-synaptic MC4R neurons in the DMH elicited exactly opposite phenotypes. Rapid deletion of LepR from AgRP neurons caused an obesity phenotype which can be rescued by blockage of GABAA receptor in the DMH. Consistent with behavioral results, these DMH neurons displayed suppressed neural activities in response to hunger or hyperglycemia. Furthermore, we identified that α3-GABAA receptor signaling within the DMH exerts potent bi-directional regulation of the central effects of leptin on feeding and body weight. Together, our results demonstrate a novel GABAergic neural circuit governing leptinmediated feeding and energy balance via a unique α3-GABAA signaling within the secondary leptinresponsive neural circuit, constituting a new avenue for therapeutic interventions in the treatment of obesity and associated comorbidities. [ABSTRACT FROM AUTHOR]

It is well established that decreases in plasma leptin levels, as with fasting, signal starvation and elicit appropriate physiological responses, such as increasing the drive to eat and decreasing energy expenditure. These responses are mediated largely by suppression of the actions of leptin in the hypothalamus, most notably on arcuate nucleus (ArcN) orexigenic neuropeptide Y neurons and anorexic pro-opiomelanocortin neurons. However, the question addressed in this review is whether the effects of increased leptin levels are also significant on the long-term control of energy balance, despite conventional wisdom to the contrary. We focus on leptin's actions (in both lean and obese individuals) to decrease food intake, increase sympathetic nerve activity, and support the hypothalamic–pituitary–thyroid axis, with particular attention to sex differences. We also elaborate on obesity-induced inflammation and its role in the altered actions of leptin during obesity. [ABSTRACT FROM AUTHOR]

BACKGROUND: Rheumatoid arthritis is an inflammatory disease with a circadian variation of symptoms. Moxibustion has achieved remarkable efficacy in the treatment of rheumatoid arthritis, but it is unclear whether the specific mechanism is related to the regulation of the clock gene and the inhibition of pyroptosis. OBJECTIVE: To explore the effects of moxibustion at different time points on core clock genes Clock, Bmal1 and pyroptosis in rats with rheumatoid arthritis. METHODS: Forty adult Sprague-Dawley rats of both sexes were randomized into a control group, a model group, a moxibustion at 7:00-9:00 A.M. group and a moxibustion at 5:00-7:00 P.M. group, with 10 rats in each group. To establish the rheumatoid arthritis model, the rats were injected with Freund’s Complete Adjuvant at the right foot. Rats in the control group were given the normal saline at the right foot. At the 7th after modeling, the two moxibustion groups began to be treated with moxibustion at Zusanli and Shenshu acupoints at 7:00-9:00 A.M. or 5:00-7:00 P.M., once a day, for total 18 treatments with a 1-day break every 6 days. We measured the right foot volume of rats using drainage method before model establishment, after model establishment and after treatment. The hypothalamus and the synovium of the right knee joint were collected from the rats after treatment. The expressions of Clock, Bmal1, Nodlike receptor family pyrin domain-containing 3 (NLRP3), Caspase-1, and Gasdermin D (GSDMD) in the hypothalamus or knee synovium were tested by real-time fluorescence quantitative PCR and western blot. RESULTS AND CONCLUSION: The mRNA expreession of Clock and BMAL1 in the hypothalamus had no obvious change among the four groups (P > 0.05). The relative mRNA expression of Clock and Bmal in the hypothalamus was higher than that in the synovium (P < 0.01). The expression of Clock and Bmal1 in the synovium was significantly down-regulated in the model group compared with the control group (P < 0.01). Moxibustion significantly increased the mRNA and protein expression of Clock and Bmal1 in the synoviums compared with the model group (P < 0.05). Compared with the moxibustion at 7:00-9:00 A.M. group, the mRNA and protein expressions of Clock and Bmal1 in the moxibustion at 5:00-7:00 P.M. group were slightly but insignificantly up-regulated (P > 0.05). The mRNA expressions of NLRP3, Caspase-1 and GSDMD in the synovium were significantly increased in the model group compared with the control group (P < 0.01). Compared with the model group, moxibustion at 5:00-7:00 P.M. could significantly reduce the relative mRNA expression of NLRP3, Caspase-1 and GSDMD in the synovium (P < 0.01). Compared with the moxibustion at 7:00-9:00 A.M. group, the relative mRNA expressions of NLRP3 and Caspase-1 were significantly lowered in the moxibustion at 5:00-7:00 P.M. group (P < 0.05, P < 0.01). All these findings indicate that moxibustion can treat rheumatoid arthritis rats by upregulating the expression of Clock and Bmal1 mRNA and protein in different tissues, down-regulating the mRNA expression of NLRP3, Caspase-1 and GSDMD in the classical signal pathway of pyroptosis, and reducing synovitis and pyroptosis. The anti-inflammatory mechanism of core clock genes Clock and BMAL1 in rheumatoid arthritis may be related to the inhibition of pyrolytic effectors. [ABSTRACT FROM AUTHOR]

BACKGROUND: Bone metabolism has always been a hotspot in bone tissue engineering research. With the deepening of the mechanism, it has been found that hypothalamus is the main regulatory center for exercise to improve bone metabolism. OBJECTIVE: To review the role of hypothalamus in bone metabolism and to explore the mechanism of exercise-mediated hypothalamus to improve bone metabolism. METHODS: A computer-based search of CNKI and PubMed databases was performed for relevant articles published from January 1983 to December 2021 with “exercise; hypothalamus; bone metabolism” as keywords both in Chinese and English. The documents that did not meet the inclusion criteria were excluded, and the 72 selected documents were summarized. RESULTS AND CONCLUSION: The hypothalamus is the key to regulating the body’s physiological activity and the downstream of the hypothalamus-pituitarytarget gland axis plays an important regulatory roleto influence hormone secretion, such as neuropeptide Y, leptin, osteocalcin and calcitonin, thus regulating regulatory factors and signaling pathways for bone metabolism, and further improving common bone diseases, such as osteoporosis. In recent years, the bonebuilding effect mediated by “brain-bone” crosstalk has received widespread attention in medicine, biology and sports science, but its specific occurrence and mechanism of action are still under investigation. Exercise activates bone metabolic signaling pathways through mechanical force stimulation and conduction of intracellular electrical signals. [ABSTRACT FROM AUTHOR]

Others have shown that leptin and cholecystokinin (CCK) act synergistically to suppress food intake. Experiments described here tested whether leptin in the ventromedial hypothalamus (VMH) contributes to the synergy with peripheral CCK in male Sprague Dawley rats. A subthreshold injection of 50-ng leptin into the VMH 1 h before a peripheral injection of 1 µg/kg CCK did not change the response to CCK in rats offered chow or low-fat purified diet, but did exaggerate the reduction in intake of high-fat diet 30 min and 1 h after injection in rats that had been food deprived for 8 h. By contrast, deletion of leptin receptor-expressing cells in the VMH using leptin-conjugated saporin (Lep-Sap) abolished the response to peripheral CCK in chow-fed rats. Lateral ventricle injection of 2-µg leptin combined with peripheral CCK exaggerated the inhibition of chow intake for up to 6 h in control rats treated with Blank-saporin, but not in Lep-Sap rats. Blank-Saporin rats offered low- or high-fat purified diet also demonstrated a dose-response inhibition of intake that reached significance with 1 µg/kg of CCK for both diets. CCK did not inhibit intake of Lep-Sap rats in either low- or high-fat-fed rats. Thus, although basal activation of VMH leptin receptors makes a significant contribution to the synergy with CCK, increased leptin activity in the VMH does not exaggerate the response to CCK in intact rats offered low-fat diets, but does enhance the response in those offered high-fat diet. [ABSTRACT FROM AUTHOR]

Leptin exerts its effects on energy balance by inhibiting food intake and increasing energy expenditure via leptin receptors in the hypothalamus. While LepR neurons in the arcuate nucleus of the hypothalamus, the primary target of leptin, have been extensively studied, LepR neurons in other hypothalamic nuclei remain understudied. LepR neurons in the lateral hypothalamus contribute to leptin's effects on food intake and reward, but due to the low abundance of this population it has been difficult to study their molecular profile and responses to energy deficit. We here explore the transcriptome of LepR neurons in the LH and their response to energy deficit. Male LepR-Cre mice were injected in the LH with an AAV carrying Cre-dependent L10:GFP. Few weeks later the hypothalami from fed and food-restricted (24-h) mice were dissected and the TRAP protocol was performed, for the isolation of translating mRNAs from LepR cells in the LH, followed by RNA sequencing. After mapping and normalization, differential expression analysis was performed with DESeq2. We confirm that the isolated mRNA is enriched in LepR transcripts and other known neuropeptide markers of LepRLH neurons, of which we investigate the localization patterns in the LH. We identified novel markers of LepRLH neurons with association to energy balance and metabolic disease, such as Acvr1c, Npy1r, Itgb1, and genes that are differentially regulated by food deprivation, such as Fam46a and Rrad. Our dataset provides a reliable and extensive resource of the molecular makeup of LH LepR neurons and their response to food deprivation. [ABSTRACT FROM AUTHOR]

Obesity is a growing worldwide health problem, affecting many people due to excessive saturated fat consumption, lack of exercise, or a sedentary lifestyle. Leptin is an adipokine secreted by adipose tissue that increases in obesity and has central actions not only at the hypothalamic level but also in other regions and nuclei of the central nervous system (CNS) such as the cerebral cortex and hippocampus. These regions express the long form of leptin receptor LepRb, which is the unique leptin receptor capable of transmitting complete leptin signaling, and are the first regions to be affected by chronic neurocognitive deficits, such as mild cognitive impairment (MCI) and Alzheimer's Disease (AD). In this review, we discuss different leptin resistance mechanisms that could be implicated in increasing the risk of developing AD, as leptin resistance is frequently associated with obesity, which is a chronic low-grade inflammatory state, and obesity is considered a risk factor for AD. Key players of leptin resistance are SOCS3, PTP1B, and TCPTP whose signalling is related to inflammation and could be worsened in AD. However, some data are controversial, and it is necessary to further investigate the underlying mechanisms of the AD-causing pathological processes and how altered leptin signalling affects such processes. [ABSTRACT FROM AUTHOR]

To explore the feeding regulatory mechanism of the leptin gene and its receptor, the full‐length cDNA of Tbleptin‐B and TbleptinR were cloned from Trachinotus blochii, and their expression patterns in different dietary strategies were analysed. The preprandial expressions of Tbleptin‐A, Tbleptin‐B and TbleptinR in liver showed a downward trend as a function of time. However, 1 h after postprandial, Tbleptin‐A increased significantly, Tbleptin‐B decreased significantly, TbleptinR did not change, and their postprandial expressions were not significantly different with the control group at 3 h. This result indicated that Tbleptin‐A and Tbleptin‐B were involved in the postprandial regulation of liver within 3 h. Similarly, the expressions of Tbleptin‐A, Tbleptin‐B and TbleptinR in liver were not different from the control group after refeeding (d11), which showed that the expressions of them in liver would return to normal level after long‐term hungry golden pomfret getting enough food. In hypothalamus, the postprandial expressions of Tbleptin‐B and TbleptinR were significantly increased at 1 h, while Tbleptin‐A was inhibited. Similarly, after refeeding, the expression of Tbleptin‐A was significantly lower than that of the control group, and Tbleptin‐B was significantly higher than that of the control group. In summary, Tbleptin‐A, Tbleptin‐B and TbleptinR play different roles in coping with different dietary strategies in liver and hypothalamus. Tbleptin‐A is mainly involved in dietary regulation through liver, while Tbleptin‐B and TbleptinR are mainly active in the hypothalamus. These results provide valuable information to reveal the T. blochii feeding regulatory mechanism. [ABSTRACT FROM AUTHOR]

Leptin irresponsiveness, which is often associated with obesity, can have significant impacts on the hypothalamic proteome of individuals, including those who are lean. While mounting evidence on leptin irresponsiveness has focused on obese individuals, understanding the early molecular and proteomic changes associated with deficient hypothalamic leptin signaling in lean individuals is essential for early intervention and prevention of metabolic disorders. Leptin receptor antagonists block the binding of leptin to its receptors, potentially reducing its effects and used in cases where excessive leptin activity might be harmful. In this work, we blocked the central actions of leptin in lean male adult Wistar rat by chronically administering intracerebroventricularly the superactive leptin receptor antagonist (SLA) (D23L/L39A/D40A/F41A) and investigated its impact on the hypothalamic proteome using label-free sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) for quantitative proteomics. Our results show an accumulation of proteins involved in mRNA processing, mRNA stability, and translation in the hypothalamus of SLA-treated rats. Conversely, hypothalamic leptin signaling deficiency reduces the representation of proteins implicated in energy metabolism, neural circuitry, and neurotransmitter release. The alterations in the adult rat hypothalamic proteome contribute to dysregulate appetite, metabolism, and energy balance, which are key factors in the development and progression of obesity and related metabolic disorders. Additionally, using bioinformatic analysis, we identified a series of transcription factors that are potentially involved in the upstream regulatory mechanisms responsible for the observed signature. • Deficient central leptin signaling induced by SLA alters hypothalamic proteomics. • Hypothalamic leptin signaling deficiency signals a state of negative energy balance. • Hypothalamic dysregulation of NMDARs postsynaptic events from SLA infused adult rats. • TAF1, Myc and YY1 transcription factors potentially regulate hypothalamic proteomics. [ABSTRACT FROM AUTHOR]

[Display omitted] Leptin is a hormone that is secreted by adipocytes in proportion to adipose tissue size, and that informs the brain about the energy status of the body. Leptin acts through its receptor LepRb, expressed mainly in the hypothalamus, and induces a negative energy balance by potent inhibition of feeding and activation of energy expenditure. These actions have led to huge expectations for the development of therapeutic targets for metabolic complications based on leptin-derived compounds. However, the majority of patients with obesity presents elevated leptin production, suggesting that in this setting leptin is ineffective in the regulation of energy balance. This resistance to the action of leptin in obesity has led to the development of "leptin sensitizers," which have been tested in preclinical studies. Much research has focused on generating combined treatments that act on multiple levels of the gastrointestinal-brain axis. The gastrointestinal-brain axis secretes a variety of different anorexigenic signals, such as uroguanylin, glucagon-like peptide-1, amylin, or cholecystokinin, which can alleviate the resistance to leptin action. Moreover, alternative mechanism such as pharmacokinetics, proteostasis, the role of specific kinases, chaperones, ER stress and neonatal feeding modifications are also implicated in leptin resistance. This review will cover the current knowledge regarding the interaction of leptin with different endocrine factors from the gastrointestinal-brain axis and other novel mechanisms that improve leptin sensitivity in obesity. [ABSTRACT FROM AUTHOR]

Leptin reduces the motivation to obtain food by modulating activity of the mesolimbic dopamine (DA) system upon presentation of cues that predict a food reward. Although leptin directly reduces the activity of ventral tegmental area (VTA) DA neurons, the majority of leptin receptor (LepR)-expressing DA neurons do not project to the nucleus accumbens, the projection implicated in driving food reward seeking. Therefore, the precise locus of leptin action to modulate motivation for a food reward is unresolved. We used transgenic mice expressing Cre recombinase under the control of the LepR promoter, anatomical tracing, optogenetics-assisted patch-clamp electrophysiology, in vivo optogenetics with fiber photometric calcium measurements, and chemogenetics to unravel how leptin-targeted neurocircuitry inhibits food reward seeking. A large number of DA neurons projecting to the nucleus accumbens are innervated by local VTA LepR-expressing GABA (gamma-aminobutyric acid) neurons. Leptin enhances the activity of these GABA neurons and thereby inhibits nucleus accumbens–projecting DA neurons. In addition, we find that lateral hypothalamic LepR-expressing neurons projecting to the VTA are inhibited by leptin and that these neurons modulate DA neurons indirectly via inhibition of VTA GABA neurons. In accordance with such a disinhibitory function, optogenetically stimulating lateral hypothalamic LepR projections to the VTA potently activates DA neurons in vivo. Moreover, we found that chemogenetic activation of lateral hypothalamic LepR neurons increases the motivation to obtain a food reward only when mice are in a positive energy balance. We identify neurocircuitry through which leptin targets multiple inputs to the DA system to reduce food reward seeking. [ABSTRACT FROM AUTHOR]

Introduction: Obesity is among the most severe challenges of our era, with significant health consequences and a high economic burden for health systems. Therefore, many countries have developed political agendas to cope with this ever-rising challenge. Along with chemical medications developed to manage obesity, researchers have focused on some natural ingredients and herbal extracts that are effective in reducing weight. The current study investigated the association between Foeniculum vulgar (fennel) extracts and body weight, lipid profile, and leptin. Methods: In total, 35 adult male BALB/c mice were investigated in sham, fennel 50 mg/kg, fennel 100 mg/kg, and fennel 200 mg/kg (n=7) groups. The mice were administered fennel extracts for fourteen days while weighted at the intervention's beginning and end. Then, their weight, lipid profile, serum leptin, and expression of leptin protein in the hypothalamus were measured. Results: After providing the intervention, leptin receptor protein expression was increased in all groups, while serum leptin didn't change significantly. Moreover, a significant decrease was observed in the cholesterol dose of 100 mg/kg/day, triglycerides in 100 and 200 mg/kg/day, and LDL in 50 and 100 mg/kg/day. Serum HDL was increased significantly in a dose of 100 mg/kg/day. Conclusion: Fennel extract can decrease the lipid profile by changing the expression of the leptin receptor. [ABSTRACT FROM AUTHOR]

Aims: Selenoproteins are an essential class of proteins involved in redox signaling and energy metabolism. However, the functions of many selenoproteins are not clearly established. Selenoprotein M (SELENOM), an endoplasmic reticulum (ER)-resident oxidoreductase bearing structural similarity to thioredoxin (TXN), is among those yet to be fully characterized. This protein is highly expressed in hypothalamic regions involved in leptin signaling and has been previously linked to energy metabolism. Herein, we performed a series of studies using in vivo and in vitro models to probe the specific influence of SELENOM on hypothalamic leptin signaling and assess SELENOM-regulated pathways. Innovation and Results: Our initial experiment in vivo demonstrated that (i) leptin promotes hypothalamic expression of SELENOM and (ii) leptin-induced STAT3 phosphorylation is impeded by SELENOM deficiency. Additional in vitro studies using mHypoE-44 immortalized hypothalamic neurons corroborated these findings, as SELENOM deficiency obstructed downstream STAT3 phosphorylation and cytosolic calcium responses evoked by leptin treatment. Correspondingly, SELENOM overexpression enhanced leptin sensitivity. Microarray analysis conducted in parallel on hypothalamic tissue and mHypoE-44 cells revealed multiple genes significantly affected by SELENOM deficiency, including thioredoxin interacting protein, a negative regulator of the TXN system. Further analysis determined that (i) SELENOM itself possesses intrinsic TXN activity and (ii) SELENOM deficiency leads to a reduction in overall TXN activity. Finally, mHypoE-44 cells lacking SELENOM displayed diminished activation of the nuclear factor kappa-light-chain enhancer of activated B-cells (NF-κB) signaling pathway and increased susceptibility to ER stress-mediated cell death. Conclusion: In sum, these findings establish SELENOM as a positive regulator of leptin signaling and TXN antioxidant activity in the hypothalamus. Antioxid. Redox Signal. 35, 775–787. [ABSTRACT FROM AUTHOR]

The trimethylation on histone H3 lysine 27 (H3k27me3), a transcriptionally repressive epigenetic mark of permissive chromatin, can be removed by the histone lysine demethylase 6a (Kdm6a). However, the physiological function of H3k27me3 and Kdm6a on circadian genes remains largely elusive. With the ChIP‐Seq and mRNA microarray assays, a critical role is identified for Kdm6a in the regulation of H3k27me3 to impact the expression of Crytochrome 1 (Cry1) in the hypothalamus of diet induced obesity mice. More importantly, both conditional knockout and pharmacological inhibition of Kdm6a reduce body weight and stabilize blood glucose homeostasis. Although a Kdm6a inhibitor fails to decrease body weight in leptin receptor‐deficient db/db mice, it significantly decreases Cry1 expression, enhances sensitivity to exogenous leptin administration, and blocks body weight increases in endo‐leptin‐deficient ob/ob mice. Moreover, gene analysis of the human hypothalamus further reveals a positive correlation between Kdm6a and Cry1. The results show that inhibition of Kdm6a reduces the Cry1 expression and sensitizes leptin signaling to combat obesity‐related disease. Therefore, it implicates Kdm6a as an attractive drug target for obesity and metabolic disorders. [ABSTRACT FROM AUTHOR]

Zucker diabetic fatty (ZDF) rats that harbor a mutation in the leptin receptor innately develop type 2 diabetes (T2D) with obesity. Transcutaneous auricular vagal nerve stimulation (taVNS) has an antidiabetic effect in ZDF rats. However, the underlying mechanisms of the weight-gain attenuating effect in ZDF rats by taVNS is still unclear. This study aimed to assess whether the weight-gain attenuating effect of taVNS in ZDF rats is associated with changes in the central nervous system (CNS) expression of P2Y1 receptors (P2Y1R). Adult male ZDF rats were subjected to taVNS and transcutaneous non-vagal nerve stimulation (tnVNS). Their food intake and body weight were recorded daily and weekly, respectively. P2Y1R expression in the hypothalamus, amygdala, and hippocampus was evaluated by western blotting. Hypothalamic P2Y1R expressing cells were detected using immunohistochemistry. Naïve ZDF rats were much heavier (p < 0.05) than their lean littermates (ZL rats), with elevated hypothalamic P2Y1R expression (p < 0.05). Further, taVNS but not tnVNS attenuated weight gain (p < 0.05) without decreasing food intake (p > 0.05) and suppressed hypothalamic P2Y1R expression in ZDF rats (p < 0.05). Moreover, P2Y1R showed major expression in astrocytes of ZDF rats' hypothalamus. ZDF rats innately develop obesity associated with elevated hypothalamic P2Y1R expression. taVNS attenuates weight gain in ZDF rats without changes in food intake, suggesting increased energy expenditure. Whether the reduced hypothalamic P2Y1R expression in response to taVNS is mechanistically linked to the increased energy expenditure remains to be determined. [ABSTRACT FROM AUTHOR]

Obesity is associated with abnormal regulation of energy metabolism in the hypothalamus. Transient receptor potential vanilloid 4 (TRPV4) is involved in regulating osmotic pressure, temperature and mechanical force transmission, but little is known about its role in obesity. Herein, the present study aimed to elucidate the effect of hypothalamic TRPV4 on high-fat diet-induced obesity (DIO) and evaluate its potential for regulating energy metabolism. Here we show that hypothalamic TRPV4 content is increased in DIO rats. Central administration of adeno-associated virus expressing TRPV4 in these animals remarkably increased body weight and fat mass by activating the S100a4/AMPKα signaling pathway, thereby promoting positive energy metabolism. Overexpressed hypothalamic TRPV4 impaired glucose tolerance, while promoting the accumulation of fat in liver cells, resulting in hepatic steatosis. In addition, the upregulation of hypothalamic TRPV4 reduces high-fat induced central inflammation. This study provides evidence that hypothalamic TRPV4 plays a significant role in regulating homeostasis. Hypothalamic TRPV4 emerges as a target for therapeutic intervention against obesity. [Display omitted] • TRPV4 is strongly upregulated in the hypothalamus of diet-induced obesity rats. • Overexpression of hypothalamic TRPV4 increases obesity susceptibility and aggravates high-fat induced obesity. • Overexpression of hypothalamic TRPV4 aggravates high-fat induced systemic energy metabolism disorder • Hypothalamic TRPV4 may be a new player in diet-induced obesity. [ABSTRACT FROM AUTHOR]

The brain plays an essential role in driving daily rhythms of behavior and metabolism in harmony with environmental light-dark cycles. Within the brain, the dorsomedial hypothalamic nucleus (DMH) has been implicated in the integrative circadian control of feeding and energy homeostasis, but the underlying cell types are unknown. Here, we identify a role for DMH leptin receptor-expressing (DMHLepR) neurons in this integrative control. Using a viral approach, we show that silencing neurotransmission in DMHLepR neurons in adult mice not only increases body weight and adiposity but also phase-advances diurnal rhythms of feeding and metabolism into the light cycle and abolishes the normal increase in dark-cycle locomotor activity characteristic of nocturnal rodents. Finally, DMHLepR-silenced mice fail to entrain to a restrictive change in food availability. Together, these findings identify DMHLepR neurons as critical determinants of the daily time of feeding and associated metabolic rhythms. [ABSTRACT FROM AUTHOR]

The vagus nerve controls motility of the GI tract and gastric acid secretion. This innovative and well-performed study improves knowledge of the impact of diet, e.g. HFD, in perinatal conditions on the vagal brain-gut response to stress and opens mechanistic, therapeutic and appropriate intervention avenues. Keywords: high fat diet; hypothalamus; vagus nerve EN high fat diet hypothalamus vagus nerve 2757 2758 2 07/18/23 20230715 NES 230715 There is a growing incidence of obesity worldwide and ~30% of mothers were obese in the USA in 2019. [Extracted from the article]

The nucleus of the solitary tract (NTS) is critical for the central integration of signals from visceral organs and contains preproglucagon (PPG) neurons, which express leptin receptors in the mouse and send direct projections to the paraventricular nucleus of the hypothalamus (PVH). Here, we visualized projections of PPG neurons in leptin-deficient Lepob/ob mice and found that projections from PPG neurons are elevated compared with controls, and PPG projections were normalized by targeted rescue of leptin receptors in LepRbTB/TB mice, which lack functional neuronal leptin receptors. Moreover, Lepob/ob and LepRbTB/TB mice displayed increased levels of neuronal activation in the PVH following vagal stimulation, and whole-cell patch recordings of GLP-1 receptor-expressing PVH neurons revealed enhanced excitatory neurotransmission, suggesting that leptin acts cell autonomously to suppress representation of excitatory afferents from PPG neurons, thereby diminishing the impact of visceral sensory information on GLP-1 receptor-expressing neurons in the PVH. [ABSTRACT FROM AUTHOR]

• Amylin and leptin signaling interact to control food intake and energy metabolism. • Variation in leptin levels during pregnancy-lactation indicate an adaptive state. • Amylin production is increased in brain areas controlling maternal behavior. • Leptin increases neurogenesis while amylin is involved in microglia cell birth. • Amylin and leptin both act as neurotrophic factors in the VMH and the AP. Amylin is co-secreted with insulin by pancreatic β-cells in response to a meal and produced by neurons in discrete hypothalamic brain areas. Leptin is proportionally secreted by the adipose tissue. Both hormones control food intake and energy homeostasis post-weaning in rodents. While amylin's main site of action is located in the area postrema (AP) and leptin's is located in the mediobasal hypothalamus, both hormones can also influence the other's signaling pathway; amylin has been shown enhance hypothalamic leptin signaling, and amylin signaling in the AP may rely on functional leptin receptors to modulate its effects. These two hormones also play major roles during other life periods. During pregnancy, leptin levels rise as a result of an increase in fat depot resulting in gestational leptin-resistance to prepare the maternal body for the metabolic needs during fetal development. The role of amylin is far less studied during pregnancy and lactation, though amylin levels seem to be elevated during pregnancy relative to insulin. Whether amylin and leptin interact during pregnancy and lactation remains to be assessed. Lastly, during brain development, amylin and leptin are major regulators of cell birth during embryogenesis and act as neurotrophic factors in the neonatal period. This review will highlight the role of amylin and leptin, and their possible interaction, during these dynamic time periods of pregnancy, lactation, and early development. [ABSTRACT FROM AUTHOR]

Previous studies indicate that leptin regulates the hypothalamic‐pituitary‐thyroid (HPT) axis via direct and indirect mechanisms. The indirect mechanism involves leptin action in pro‐opiomelanocortin (POMC)‐ and agouti‐related peptide (AgRP)‐expressing neurones. These cells innervate the paraventricular nucleus of the hypothalamus (PVH) where they modulate hypophysiotrophic thyrotrophin‐releasing hormone (TRH)‐producing neurones. The direct mechanism involves the expression of leptin receptor (LepR) in a subpopulation of PVH TRH neurones. However, to our knowledge, the existence of LepR in PVH TRH neurones of mice has not been clearly confirmed. Therefore, we investigated possible species‐specific differences between rats and mice with respect to the mechanisms recruited by leptin to regulate the HPT axis. We observed that an acute leptin injection induced phosphorylated signal transducer and activator of transcription 3 (pSTAT3), a marker of leptin‐responsive cells, in 46.2 ± 8.0% of PVH proTRH immunoreactive neurones in rats. By contrast, an insignificant number of proTRH positive neurones in the mouse PVH co‐expressed leptin‐induced pSTAT3 or LepR. Similarly, central leptin injection increased the percentage of PVH proTRH neurones containing cAMP response element‐binding protein phosphorylation in rats, but not in mice. We investigated the innervation of AgRP and POMC axons in the PVH and observed that rats exhibited a denser POMC innervation in the PVH compared to mice, whereas rats and mice showed similar density of AgRP axons in the PVH. In conclusion, rats and mice exhibit important species‐specific differences in the direct and indirect mechanisms used by leptin to regulate the HPT axis. [ABSTRACT FROM AUTHOR]

High altitude hypobaric hypoxia environment impairs male's reproductive function. Leptin is an adipose tissue-derived hormone which regulates body weight homeostasis. Its receptor (LepR) has been found in all levels of male reproductive axis, indicating that it can affect male reproductive system in a direct or (and) indirect way. However, the role of leptin signaling in hypobaric hypoxia induced male reproductive dysfunction remains to be elucidated. In this study, we investigated the changes of leptin levels in male SD rats in stimulated altitude of 5500 m hypobaric hypoxia environment and their effects on the hypothalamus-pituitary-gonad axis (HPG axis). A hypoxia animal model was established using a hypobaric hypoxia chamber. Rats were divided randomly into 1, 7, 14, 28-day hypoxia group, recovery group (14 days hypoxia+14 days normoxia) and their control groups. Hypoxia groups displayed obvious changes of testicular and epididymis index compared to control groups. The total number of sperm and sperm motility rate decreased dramatically, while sperm deformity rate increased in hypoxia groups. The flow cytometry analysis showed that the percentage of haploid in 1-day, 7-day and 28-day hypoxia groups increased while the proportion of diploid decreased in 14-day and 28-day hypoxia group. TUNEL staining showed that the testis cells apoptosis index (AI) of hypoxia groups increased significantly, and the apoptosis of cells mainly focus on spermatogonia and spermatocytes. The expression of GnRH in hypothalamus decreased dramatically under hypoxia condition, accompanied with the reduction of serum testosterone (T) level in 1-day and 28-day hypoxia groups and free-testosterone level (FT) in 1-day and 14-day hypoxia groups. Importantly, ELISA analysis showed that serum leptin level decreased in 7-day hypoxia groups and acylated-ghrelin, gastrin also changed, accompanying with reduction of LepR in hypothalamus in hypoxia groups. Immunohistochemical staining exhibited increased leptin and LepR in testis under hypobaric hypoxia conditions. Our results suggested that simulated high altitude hypobaric hypoxia environment decreased male reproductive function, depressed HPG axis activity and altered the serum concentration of hormones related to food intake in adult male rats. Additionally, hypobaric hypoxia induced the leptin-LepR expression in adult male rats' testis, suggesting leptin-LepR signaling may mediate hypoxia-induced impairment in male rats' reproductive system. • Hypoxia alters the serum concentration of leptin. • Leptin receptor is expressed in all levels of male reproductive axis. • Hypoxia changes the leptin receptor's expression in HPG axis. • Leptin-LepR may mediate hypoxia-induced impairment in male's reproductive system. [ABSTRACT FROM AUTHOR]

Leptin, secreted by peripheral adipocytes, binds the leptin receptor (Lepr) in the hypothalamus, thereby contributing to the regulation of satiety and body weight. Lepr is expressed in the embryonic brain as early as embryonic day 12.5. However, the function of Lepr in neural precursor cells in the brain has not been resolved. To address this issue, we crossed the Leprflox/flox mice with each of Shh-Cre mice (Shh, sonic hedgehog) and Nestin (Nes)-Cre mice. We found that deletion of Lepr specifically in nestin-expressing cells led to extreme obesity, but the conditional null of Lepr in Shh-expressing cells had no obvious phenotype. Moreover, the level of leptin-activated pSTAT3 decreased in the anterior and central subregions of the arcuate hypothalamus of Shh-Cre; Leprflox/flox mice compared with the controls. By contrast, in Nes-Cre; Leprflox/flox mice, the level of leptin-activated pSTAT3 decreased in all subregions including the anterior, central, and posterior arcuate hypothalamus as well as the dorsomedial, ventromedial, and median eminence of the hypothalamus, revealing that the extensive lack of Lepr in the differentiated neurons of the hypothalamus in the conditional null mice. Notably, conditional deletion of Lepr in nestin-expressing cells enhanced the differentiation of neural precursor cells into neurons and oligodendroglia but inhibited differentiation into astrocytes early in postnatal development of hypothalamus. Our results suggest that Lepr expression in neural precursor cells is essential for maintaining normal body weight as well as the differentiation of neural precursor cells to the neural/glial fate in the hypothalamus shortly after birth. [ABSTRACT FROM AUTHOR]

Leptin signaling pathways, stemming primarily from the hypothalamus, are necessary for maintaining normal energy homeostasis and body weight. In both rodents and humans, dysregulation of leptin signaling leads to morbid obesity and diabetes. Since leptin resistance is considered a primary factor underlying obesity, understanding the regulation of leptin signaling could lead to therapeutic tools and provide insights into the causality of obesity. While leptin actions in some hypothalamic regions such as the arcuate nuclei have been characterized, less is known about leptin activity in the hypothalamic ventromedial nuclei (VMN). Recently, pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to reduce feeding behavior and alter metabolism when administered into the VMN in a pattern similar to that of leptin. In the current study, we examined whether leptin and PACAP actions in the VMN share overlapping pathways in the regulation of energy balance. Interestingly, PACAP administration into the VMN increased STAT3 phosphorylation and SOCS3 mRNA expression, both of which are hallmarks of leptin receptor activation. In addition, BDNF mRNA expression in the VMN was increased by both leptin and PACAP administration. Moreover, antagonizing PACAP receptors fully reversed the behavioral and cellular effects of leptin injections into the VMN. Electrophysiological studies further illustrated that leptin-induced effects on VMN neurons were blocked by antagonizing PACAP receptors. We conclude that leptin dependency on PACAP signaling in the VMN suggests a potential common signaling cascade, allowing a tonically and systemically secreted neuropeptide to be more precisely regulated by central neuropeptides. [ABSTRACT FROM AUTHOR]

Guanylyl cyclase C (GUCY2C) is the afferent central receptor in the gut–brain endocrine axis regulated by the anorexigenic intestinal hormone uroguanylin. GUCY2C mRNA and protein are produced in the hypothalamus, a major center regulating appetite and metabolic homeostasis. Further, GUCY2C mRNA and protein are expressed in the ventral midbrain, a principal structure regulating hedonic reward from behaviors including eating. While GUCY2C is expressed in hypothalamus and midbrain, its precise neuroanatomical organization and relationship with circuits regulating satiety remain unknown. Here, we reveal that hypothalamic GUCY2C mRNA is confined to the ventral premammillary nucleus (PMV), while in midbrain it is produced by neurons in the ventral tegmental area (VTA) and substantia nigra (SN). GUCY2C in the PMV is produced by 46% of neurons expressing anorexigenic leptin receptors, while in the VTA/SN it is produced in most tyrosine hydroxylase-immunoreactive neurons. In contrast to mRNA, GUCY2C protein is widely distributed throughout the brain in canonical sites of PMV and VTA/SN axonal projections. Selective stereotaxic ablation of PMV or VTA/SN neurons eliminated GUCY2C only in their respective canonical projection sites. Conversely, specific anterograde tracer analyses of PMV or VTA/SN neurons confirmed distinct GUCY2C-immunoreactive axons projecting to those canonical locations. Together, these findings reveal two discrete neuronal circuits expressing GUCY2C originating in the PMV in the hypothalamus and in the VTA/SN in midbrain, which separately project to other sites throughout the brain. They suggest a structural basis for a role for the GUCY2C-uroguanylin gut–brain endocrine axis in regulating homeostatic and behavioral components contributing to satiety. [ABSTRACT FROM AUTHOR]

Background: Obesity is associated with reduced physiological responses to leptin and insulin, leading to the concept of obesity-associated hormonal resistance. Objectives: Here, we demonstrate that contrary to expectations, leptin signaling not only remains functional but also is constantly activated in the arcuate nucleus of the hypothalamus (ARH) neurons of obese mice. This state of persistent response to endogenous leptin underpins the lack of response to exogenous leptin. Methods and Results: The study of combined leptin and insulin signaling demonstrates that there is a common pool of ARH neurons responding to both hormones. More importantly, we show that the constant activation of leptin receptor neurons in the ARH prevents insulin signaling in these neurons, leading to impaired glucose tolerance. Accordingly, antagonising leptin signaling in diet-induced obese (DIO) mice restores insulin signaling in the ARH and improves glucose homeostasis. Direct inhibition of PTP1B in the CNS restores arcuate insulin signaling similarly to leptin inhibition; this effect is likely to be mediated by AgRP neurons since PTP1B deletion specifically in AgRP neurons restores glucose and insulin tolerance in DIO mice. Conclusions: Finally, our results suggest that the constant activation of arcuate leptin signaling in DIO mice increases PTP1B expression, which exerts an inhibitory effect on insulin signaling leading to impaired glucose homeostasis. [ABSTRACT FROM AUTHOR]

Leptin administration into the hindbrain, and specifically the nucleus of the solitary tract, increases phosphorylated signal transducer and activator of transcription 3 (pSTAT3), a marker of leptin receptor activation, in hypothalamic nuclei known to express leptin receptors. The ventromedial nucleus of the hypothalamus (VMH) shows the greatest response, with a threefold increase in pSTAT3. This experiment tested the importance of VMH leptin receptor-expressing neurons in mediating weight loss caused by fourth ventricle (4V) leptin infusion. Male Sprague-Dawley rats received bilateral VMH 75-nL injections of 260 ng/μL of leptin-conjugated saporin (Lep-Sap) or blank-saporin (Blk-Sap). After 23 days they were fitted with 4V infusion cannulas and 1 wk later adapted to housing in a calorimeter before they were infused with 0.9 μg leptin/day for 14 days. There was no effect of VMH Lep-Sap on weight gain or glucose clearance before leptin infusion. Leptin inhibited food intake and respiratory exchange ratio in Blk-Sap but not Lep-Sap rats. Leptin had no effect on energy expenditure or brown adipose tissue temperature of either group. Inguinal and epididymal fat were significantly reduced in leptin-treated Blk-Sap rats, but the response was greatly attenuated in Lep-Sap rats. VMH pSTAT3 was increased in leptin-treated Blk-Sap but not Lep-Sap rats. These results support the concept that leptininduced weight loss results from an integrated response across different brain areas. They also support previous reports that VMH leptin receptors do not play a significant role in maintaining energy balance in basal conditions but limit weight gain during positive energy balance. [ABSTRACT FROM AUTHOR]

Leptin, a hormone mainly produced by adipocytes in proportion to fat mass, is a key component in the regulation of energy homeostasis and reproductive, neuroendocrine, immune, and metabolic functions. Leptin binds to the leptin receptor, which is expressed throughout the central nervous system but particularly in neurons of several nuclei of the hypothalamus, such as the arcuate nucleus (ARC) and paraventricular nucleus (PVN). It has been found that nitric oxide (NO) plays an important role in mediating effects of leptin. Since PVN and ARC neurons are known to express leptin receptors, we investigated the effects of leptin on nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) reactivity in the PVN and ARC of male Wistar rats. Our results have shown that systemic administration of leptin resulted in increased NADPH-d positive cell number in the PVN and ARC, suggesting that both the PVN and ARC may be important centers in the hypothalamus for the leptin action, mediated by increased NO production. In addition, we have also observed that hypothalamic tanycytes in the ventral portion of the third ventricle were NADPH-d positive. We speculate that leptin may affect the release of neurohormones and hypothalamic neurogenesis by activating nitric oxide synthase in hypothalamic tanycytes. [ABSTRACT FROM AUTHOR]

Leptin is an adipokine that regulates adipose tissue mass through membrane-anchored leptin receptor (Ob-R). Extracellular domain of Ob-R in plasma is called soluble leptin receptor (sOb-R), and is the main leptin-binding protein. Based on a previous DNA microarray analysis that showed induction of hepatic Ob-R mRNA in low-protein diet-fed mice, this study aimed to clarify the effect of dietary protein restriction on hepatic Ob-R mRNA and plasma sOb-R levels. First, the effect of protein restriction on hepatic Ob-R mRNA level was examined together with fasting and food restriction using male rats as common experimental model for nutritional research. Hepatic Ob-R mRNA level was increased by feeding low-protein diet for 7 d, although not significantly influenced by 12-h fasting and sixty percent restriction in food consumption. Then, effect of protein restriction on liver Ob-R and plasma sOb-R was investigated using male mice because specific sOb-R ELISA was more available for mice. Hepatic Ob-R mRNA level was also increased in protein restricted-mice although it did not increase in hypothalamus. Hepatic Ob-R protein was decreased, whereas plasma sOb-R was increased by protein restriction. Because the concentration of sOb-R increased without changing plasma leptin concentration, free leptin in plasma was significantly reduced. The direct effect of amino acid deprivation on Ob-R mRNA level was not observed in rat hepatoma cells H4IIE cultured in amino acid deprived medium. In conclusion, dietary protein restriction increased hepatic Ob-R mRNA, resulting in increased plasma sOb-R concentration, which in turn, reduces plasma free leptin level and may modulate leptin activity. [ABSTRACT FROM AUTHOR]

Photoperiod is believed to regulate growth in fish, although the mechanism involved is still unclear. In this paper, we report a relationship between leptin-receptor A1 (AsLRa1), melatonin-receptor (AsMR) and photoperiod in Atlantic salmon. Atlantic salmon (mean weight 1071.70 ± 155.54 g) were reared under six photoperiod regimes, four constant light regimes 24L:0D, 18L:6D, 12L:12D and 8L:16D, hours of light (L) and dark (D) and two varying light regimes, LL-SL = 24L:0D-8L:16D, and SL-LL = 8L:16D-24L:0D over a period of seven months. The results showed that AsLRa1 transcripts were mainly existed in the hypothalamus and saccus vasculosus (SV), AsMR was mainly expressed in the hypothalamus. Long photoperiod inhibited the expression of AsLRa1 and AsMR transcripts in the Atlantic salmon brain. The expression pattern of AsLRa1 was similar to the expression pattern of AsMR in the hypothalamus. Food intake was higher in fish with lower AsLRa1 transcript levels. This demonstrated that photoperiod influenced somatic growth by changing expression of AsLRa1 in the hypothalamus and SV to affect appetite. In addition, we found that the SV appears to act as a seasonal sensor regulating reproduction in a similar way to the hypothalamus. [ABSTRACT FROM AUTHOR]

Previous studies suggest that weight loss occurs when leptin receptors in both the forebrain and hindbrain are activated. Experiments described here tested whether this integration is mediated through a neural connection or by leptin diffusion through the subarachanoid space. If the hypothalamus and hindbrain communicated through a neural pathway, then a very low dose of leptin infused directly into the nucleus of the solitary tract (NTS) would enhance the response to third ventricle (3V) leptin but would have no effect if infused into the fourth ventricle (4V). A 12-day infusion of 10 ng/24 h into the 4V or the NTS reduced body fat. Leptin at 5 ng/24 h into the 4V or NTS had no effect on food intake or body composition, but infusion of 5 ng of leptin/24 h into the NTS combined with a 3V injection of 0.1 μg of leptin inhibited food intake between 6 and 12 h after injection. Cumulative intake was inhibited for up to 36 h. 3V leptin had no effect on food intake of rats receiving the 4V leptin infusion. Similar results were found using infusions of 5 ng leptin/24 h and a 3V injection of 0.025 μg leptin. These data suggest that activation of leptin receptors in the NTS lowers the threshold for response to leptin in the forebrain through a neural network. [ABSTRACT FROM AUTHOR]

The European beaver (Castor fiber L.) is the largest free-living rodent in Eurasia. The present work aimed to determine sex- and season-related changes in leptin receptor (Ob-R) expression in the hypothalamic–pituitary–gonadal/adrenal axes and uterus of beavers during breeding- (April), post-breeding- (July), and pre-breeding- (November) periods. The expression of Ob-R gene and protein was found in all analyzed tissues. The expression of Ob-R mRNA remained constant in the hypothalamus of both sexes during the analyzed stages. Sex- and season-related changes were found in the pituitary gland; the greatest level was observed in July in both sexes. The same expression pattern was noted in the testis, whereas in the ovary a lack of seasonal changes was found. In uterine tissues, the greatest expression occurred in November. The impact of season was also demonstrated in the adrenal cortex. In females, a higher Ob-R transcript level was noted in April, while in males, an increased mRNA abundance was noted in November than July. Our study suggests that in the beaver, leptin acting via the Ob-R can be an important endocrine factor engaged in the regulation of reproductive functions and stress response. [ABSTRACT FROM AUTHOR]

Resistin promotes hypothalamic neuroinflammation and insulin resistance through Toll like receptor 4 (TLR4), this hormone is thought to be a link between obesity and insulin-resistance. Indeed, resistin plasma levels are higher in obese and insulin resistant subjects. However, the impact of maternal resistin on the predisposition of offspring to hypothalamic neuroinflammation is unknown. Here, female mice were treated with resistin during gestation/lactation periods, then hypothalamic neuroinflammation was investigated in male offspring at p28 and p90. At p28, resistin increased the expression of inflammation markers (IL6, TNFα and NFκB) and TLR4 in the hypothalamus and decreased both hypothalamic insulin and leptin receptors’ expression. The hypothalamic up-regulation IL6, TNFα and TLR4 was sustained until p90 promoting most likely hypothalamic inflammation. Maternal resistin also increased IL6 and TNFα in the adipose tissue of offspring at p90 associated with a higher body weight gain. In contrast, liver and muscle were not affected. These findings reveal that the augmentation of maternal resistin during gestation and lactation promotes hypothalamic and adipose tissue inflammation of offspring as evidenced by sustained increase of inflammation markers from weaning to adulthood. Thus, maternal resistin programs offspring hypothalamic and adipose tissue inflammation predisposing then offspring to body weight gain. [ABSTRACT FROM AUTHOR]

Genetic evidence indicates that brain-derived neurotrophic factor (BDNF) signaling through the TrkB receptor plays a critical role in the control of energy balance. Mutations in the BDNF or the TrkBencoding NTRK2 gene have been found to cause severe obesity in humans and mice. However, it remains unknown which brain neurons express TrkB to control body weight. Here, we report that TrkBexpressing neurons in the dorsomedial hypothalamus (DMH) regulate food intake. We found that the DMH contains both glutamatergic and GABAergic TrkB-expressing neurons, some of which also express the leptin receptor (LepR). As revealed by Fos immunohistochemistry, a significant number of TrkB-expressing DMH (DMHTrkB) neurons were activated upon either overnight fasting or after refeeding. Chemogenetic activation of DMHTrkB neurons strongly suppressed feeding in the dark cycle when mice are physiologically hungry, whereas chemogenetic inhibition of DMHTrkB neurons greatly promoted feeding in the light cycle when mice are physiologically satiated, without affecting feeding in the dark cycle. Neuronal tracing revealed that DMHTrkB neurons do not innervate neurons expressing agouti-related protein in the arcuate nucleus, indicating that DMHTrkB neurons are distinct from previously identified LepR-expressing GABAergic DMH neurons that suppress feeding. Furthermore, selective Ntrk2 deletion in the DMH of adult mice led to hyperphagia, reduced energy expenditure, and obesity. Thus, our data show that DMHTrkB neurons are a population of neurons that are necessary and sufficient to suppress appetite and maintain physiological satiation. Pharmacological activation of these neurons could be a therapeutic intervention for the treatment of obesity. [ABSTRACT FROM AUTHOR]

Hypothalamic leptin receptor (LR) signaling regulates body weight by balancing food intake and energy expenditure. It is well established that the human LR undergoes ectodomain shedding, but little is known about the fate of the remaining cytosolic domain. This study demonstrates that regulated intramembrane proteolysis (RIP) releases the LR intracellular domain (LR ICD), which translocates to the mitochondria where it binds to SOCS6. This LR ICD-SOCS6 interaction stabilizes both proteins on the mitochondrial outer membrane and requires a functional BC box in SOCS6 for mitochondrial association and a central motif in the LR ICD for SOCS6 binding. The LR ICD prevents CCCP-induced mitochondrial depolarization and mitophagy as shown by lowered Parkin translocation and p62 accumulation. Strict regulation of mitochondrial dynamics in the hypothalamus is known to be essential for body weight homeostasis. This is the first study showing that the LR can directly modulate mitochondrial biology. [ABSTRACT FROM AUTHOR]

The pro-opiomelanocortin (POMC)-expressing neurons of the hypothalamic arcuate nucleus (ARC) are involved in the control of food intake and metabolic processes. It is assumed that, in addition to leptin, the activity of these neurons is regulated by serotonin and dopamine, but only subtype 2C serotonin receptors (5-HT2CR) was identified earlier on the POMC-neurons. The aim of this work was a comparative study of the localization and number of leptin receptors (LepR), types 1 and 2 dopamine receptors (D1R, D2R), 5-HT1BR and 5-HT2CR on the POMC-neurons and the expression of the genes encoding them in the ARC of the normal and diet-induced obese (DIO) rodents and the agouti mice (Ay/a) with the melanocortin obesity. As shown by immunohistochemistry (IHC), all the studied receptors were located on the POMC-immunopositive neurons, and their IHC-content was in agreement with the expression of their genes. In DIO rats the number of D1R and D2R in the POMC-neurons and their expression in the ARC were reduced. In DIO mice the number of D1R and D2R did not change, while the number of LepR and 5-HT2CR was increased, although to a small extent. In the POMC-neurons of agouti mice the number of LepR, D2R, 5-HT1BR and 5-HT2CR was increased, and the D1R number was reduced. Thus, our data demonstrates for the first time the localization of different types of the serotonin and dopamine receptors on the POMC-neurons and a specific pattern of the changes of their number and expression in the DIO and melanocortin obesity. [ABSTRACT FROM AUTHOR]

Although the short-term effects of fasting or energy deficit on hypothalamic neuropeptide circuitries are now better understood, the effects of long-term energy deficit and refeeding remain to be elucidated. We showed that after a long-term energy deficit, mice exhibited persistent hypoleptinemia following the refeeding period despite restoration of fat mass, ovarian activity, and feeding behavior. We aimed to examine the hypothalamic adaptations after 10 weeks of energy deficit and after 10 further weeks of nutritional recovery. To do so, we assessed the mRNA levels of the leptin receptor and the main orexigenic and anorexigenic peptides, and their receptors regulated by leptin. Markers of hypothalamic inflammation were assessed as leptin can also participate in this phenomenon. Long-term time-restricted feeding and separation induced significant increase in mRNA lev els of hypothalamic orexigenic peptides, while both Y1 and Y5 receptor mRNAs were downregulated. No changes occurred in the mRNA levels of orexin (OX), melanin-concentrating hormone, pro-opiomelanocortin, 26RFa (26-amino acid RF-amide peptide), and their receptors despite an increase in the expression of melanocortin receptors (MC3-R and MC4-R) and OXR1 (OX receptor 1). The refeeding period induced an overexpression of leptin receptor mRNA in the hypothalamus. The other assessed mRNA levels were normalized except for Y2, Y5, MC3-R, and MC4-R, which remained upregulated. No convincing changes were observed in neuroinflammatory markers, even if interleukin-1β mRNA levels were increased in parallel with those of Iba1 (ionized calcium-binding adaptor molecule 1), a marker of microglial activation. Normalization of leptin-regulated functions and hypothalamic gene expressions in refed mice with low plasma leptin levels could be sustained by recalibration of hypothalamic sensitivity to leptin. [ABSTRACT FROM AUTHOR]

Low-grade chronic inflammation in obesity is associated with leptin resistance. In order to alleviate this pathological condition, bioactive compounds capable of attenuating oxidative stress and inflammation have been researched, and bergamot (Citrus bergamia) presents these properties. The aim was to evaluate the effect of bergamot leaves extract on leptin resistance in obese rats. Animals were divided into 2 groups: control diet (C, n = 10) and high sugar-fat diet (HSF, n = 20) for 20 weeks. After detecting hyperleptinemia, animals were divided to begin the treatment with bergamot leaves extract (BLE) for 10 weeks: C + placebo (n = 7), HSF + placebo (n = 7), and HSF + BLE (n = 7) by gavage (50 mg/kg). Evaluations included nutritional, hormonal and metabolic parameters; adipose tissue dysfunction; inflammatory, oxidative markers and hypothalamic leptin pathway. HSF group presented obesity, metabolic syndrome, adipose tissue dysfunction, hyperleptinemia and leptin resistance compared to control group. However, the treated group showed a decrease in caloric consumption and attenuation of insulin resistance. Moreover, dyslipidemia, adipose tissue function, and leptin levels showed an improvement. At the level of the hypothalamus, the treated group showed a reduction of oxidative stress, inflammation and modulation of leptin signaling. In conclusion, BLE properties were able to improve leptin resistance through recovery of the hypothalamic pathway. [Display omitted] • Chronic inflammation present in obesity is associated with leptin resistance. • Bergamot attenuated inflammation and oxidative stress in the hypothalamus. • Bergamot leaves extract attenuated metabolic syndrome. • Bergamot leaves extract treatment recovered leptin pathway in the hypothalamus. [ABSTRACT FROM AUTHOR]

There is increasing concern about the effects of endocrine disrupting chemicals (EDCs) on human health. Recently, some EDCs are suggested to affect energy metabolism leading to increased risk of obesity. Obesogenic effects of some EDCs on adipogenesis have been reported, however, there is no study examining their potential actions on the brain circuits controlling feeding and metabolism. We have investigated effects of tributyltin (TBT) and dichlorodiphenyltrichloroethane (p,p'-DDT) on electrical activity on dorsomedial hypothalamic leptin receptor neurons (DMHLepR), morphological adaptations in neuronal anatomy of DMHLepR, locomotion, and anxiety-like behaviors in mice. Twenty-three Lep-Cre transgenic mice were intracranially injected with GFP virus. Control animals received intraperitoneal corn oil alone while group 2 and 3 received TBT (25 μg/kg) and p,p'-DDT (2 mg/kg) for one month. Locomotor activity and anxiety-like behavior of the animals were determined by open field test. Electrophysiological effects of TBT and p,p'-DDT on DMHLepR neurons were determined by patch clamp method. Neuronal anatomy was determined by confocal microscopy. Spontaneous firing frequency of DMHLepR neurons of TBT group of mice was significantly higher than both p,p'-DDT and control groups (p < 0.01). TBT and p,p'-DDT significantly decreased frequency of the spontaneous inhibitory post-synaptic currents to DMHLepR neurons compared to the control group (p < 0.05). The time spent in the center and the number of entrances to the center by the TBT-administered mice were significantly lower than other groups (p < 0.01). The total distance traveled and mean speed of the control group of mice were significantly higher than the p,p'-DDT- and TBT-administered animals (p < 0.0001). c-Fos activity of the p,p'-DDT- and TBT-administered animals were significantly elevated compared to the control group (p < 0.001), while no change in the number of dendritic spines were observed. In conclusion, this study demonstrates that exposure to TBT and p,p'-DDT alters electrical activity in DMHLepR neurons and behavioral state in mice. [Display omitted] • TBT increased the firing frequency of DMHLepR neurons. • TBT and DDT decreased frequency of sIPSC currents to DMHLepR neurons. • Chronic TBT administration increased anxiety-like behaviour. • TBT and DDT administration reduced locomotor activity. • TBT and DDT increased c-fos activity in DMHLepR neurons. [ABSTRACT FROM AUTHOR]