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Until menopause, women have a lower propensity to develop metabolic diseases than men, suggestive of a protective role for sex hormones. Although a functional synergy between central actions of estrogens and leptin has been demonstrated to protect against metabolic disturbances, the underlying cellular and molecular mechanisms mediating this crosstalk have remained elusive. By using a series of embryonic, adult-onset, and tissue/cell-specific loss-of-function mouse models, we document an unprecedented role of hypothalamic Cbp/P300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 1 (Cited1) in mediating estradiol (E2)-dependent leptin actions that control feeding specifically in pro-opiomelanocortin (Pomc) neurons. We reveal that within arcuate Pomc neurons, Cited1 drives leptin's anorectic effects by acting as a co-factor converging E2 and leptin signaling via direct Cited1-ERα-Stat3 interactions. Together, these results provide new insights on how melanocortin neurons integrate endocrine inputs from gonadal and adipose axes via Cited1, thereby contributing to the sexual dimorphism in diet-induced obesity.

During β-adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which then translocates to the nucleus to activate the expression of Ucp1 and Pgc-1α. The mechanisms underlying ATF2 target activation are unknown. Here we demonstrate that p62 (Sqstm1) binds to ATF2 to orchestrate activation of the Ucp1 enhancer and Pgc-1α promoter. P62Δ69-251 mice show reduced expression of Ucp1 and Pgc-1α with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1α expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62Δ69-251 mice, global p62−/− and Ucp1-Cre p62flx/flx mice. BAT dysfunction resulting from p62 deficiency is manifest after birth and obesity subsequently develops despite normal food intake, intestinal nutrient absorption and locomotor activity. In summary, our data identify p62 as a master regulator of BAT function in that it controls the Ucp1 pathway through regulation of ATF2 genomic binding., Beta-adrenergic stimulation of brown adipose tissue leads to thermogenesis via the activating transcription factor 2 (ATF2) mediated expression of the thermogenic genes Ucp1 and Pgc-1α. Here, the authors show that the scaffold protein p62 regulates brown adipose tissue function through modifying ATF2 genomic binding and subsequent Ucp1 and Pgc-1α induction.

Background: The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent beta-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity. Scope of review: In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases. Major conclusions: Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders (C) 2019 The Authors. Published by Elsevier GmbH.

Physiological regulation is so fundamental to survival that natural selection has greatly favored the evolution of robust regulatory systems that use both reactive and preemptive responses to mitigate the disruptive impact of biological and environmental challenges on physiological function. In good health, robust regulatory systems provide little insight into the typically hidden complex array of sensor-effector interactions that accomplish successful regulation. Numerous health disorders have been traced to defective regulatory mechanisms, and generations of scientists have worked to discover ways to correct these defects and restore normal physiological function. Despite progress, numerous chronic health disorders remain resistant to treatment, and indeed for some disorders the incidence is increasing. We propose that an individual's susceptibility to acquire certain persistent dysregulatory disorders can be traced to interindividual variation in how that individual's regulatory system responds to challenges. Preexisting reliable individual differences among regulatory systems are typically unrecognized until appropriate regulatory challenges (e.g., exposure to a drug of abuse) lead to dysregulation (e.g., drug addiction). Specific characteristics of an individual's regulatory responsiveness may include etiological factors that participate in the acquisition, escalation and maintenance of health disorders characterized by dysregulation. By appropriately challenging a healthy individual's regulatory systems to identify its underlying characteristics, it is possible to ascertain whether an individual has an elevated risk for acquiring a dysregulated health condition and thereby enable strategies designed to prevent, rather than treat, the condition. This model is applied to drug addiction, and in addition we relate this approach to other dysregulated conditions such as obesity. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Daniel Porte Jr. was born in New York City in 1931, and with his father being a clinical cardiologist, medicine was part of his life from very early on. After completing his undergraduate studies at Brown University, he commenced his migration west by first attending medical school at the University of Chicago, where he graduated with honors in 1957. Completing his westward migration, Dan moved to San Francisco for his internship and residency training in medicine in the University of California system. During that time, he spent 2 years performing research with Richard Havel at the Cardiovascular Research Institute at the University of California, San Francisco. It was during this period that Dan published his first scientific article describing cholesterol-labeled lipoproteins as a tracer for examining the fate of plasma cholesterol (1), as well as a clinical research study of an unusual patient with McArdle syndrome causing defective muscle phosphorylase leading to defective exercise tolerance (2). Daniel Porte Jr. at medical school graduation, University of Chicago, 1957 Based on this early experience, it became clear to Dan that his future lay in academia and clinical research, so he decided to travel north to the University of Washington (UW) in Seattle for fellowship training in endocrinology and metabolism. One of the academic attractants at the time was Robert H. Williams, who was a leading national force in endocrinology and Chairman of Medicine at UW. As lipids were an important area of investigation in Seattle as well as in San Francisco at the time, Dan continued to work in this area during his fellowship and early faculty years. Following the development of the insulin radioimmunoassay, however, a whole new field opened up and he moved his research in a completely new direction. Dan commenced his research in glucose metabolism and diabetes …

Despite the ability of some gastrointestinal hormones to reliably reduce meal size when administered prior to a meal, it is not understood why the repeated administration or genetic knockout of these hormones appear largely ineffective in reducing food intake and body weight. Here, we review evidence that the ability of GI peptides such as cholecystokinin (CCK) to elicit satiation is a consequence of prior learning. Evidence includes first, that the ability of some of these signals to modify food intake depends upon past experience and is malleable with new experience. Additionally, the ability of CCK and other gut signals to reduce food intake may not be hard-wired; i.e., any so-called "satiation" signal that reduces food intake in a single-meal situation may not continue to do so over repeated trials. The individual will respond to the signal only so long as it provides reliable information about caloric content. If a particular signal becomes unreliable, the individual will rely on other signals to end meals. Thus, gut peptides/hormones have important metabolic effects such as mediating absorption, digestion, and many aspects of the distribution of ingested nutrients throughout the body; and, if they have been reliably associated with natural stimuli that mediate satiation, they also inform behavior.

Meta-inflammation of hypothalamic areas governing energy homeostasis has recently emerged as a process of potential pathophysiological relevance for the development of obesity and its metabolic sequelae. The current model suggests that diet-induced neuronal injury triggers microgliosis and astrocytosis, conditions which ultimately may induce functional impairment of hypothalamic circuits governing feeding behavior, systemic metabolism, and body weight. Epidemiological data indicate that low circulating HDL levels, besides conveying cardiovascular risk, also correlate strongly with obesity. We simulated that condition by using a genetic loss of function mouse model (apoA-I(−/−)) with markedly reduced HDL levels to investigate whether HDL may directly modulate hypothalamic inflammation. Astrogliosis was significantly enhanced in the hypothalami of apoA-I(−/−) compared with apoA-I(+/+) mice and was associated with compromised mitochondrial function. apoA-I(−/−) mice exhibited key components of metabolic disease, like increased fat mass, fasting glucose levels, hepatic triglyceride content, and hepatic glucose output compared with apoA-I(+/+) controls. Administration of reconstituted HDL (CSL-111) normalized hypothalamic inflammation and mitochondrial function markers in apoA-I(−/−) mice. Treatment of primary astrocytes with apoA-I resulted in enhanced mitochondrial activity, implying that circulating HDL levels are likely important for astrocyte function. HDL-based therapies may consequently avert reactive gliosis in hypothalamic astrocytes by improving mitochondrial bioenergetics and thereby offering potential treatment and prevention for obesity and metabolic disease.

Molecular Metabolism, 14

More than one-third of the worldwide population is overweight or obese and therefore at risk of developing type 2 diabetes mellitus. In order to mitigate this pandemic, safer and more potent therapeutics are urgently required. This necessitates the continued use of animal models to discover, validate and optimize novel therapeutics for their safe use in humans. In order to improve the transition from bench to bedside, researchers must not only carefully select the appropriate model but also draw the right conclusions. In this Review, we consolidate the key information on the currently available animal models of obesity and diabetes and highlight the advantages, limitations and important caveats of each of these models.

// Ling Shen 1 , David Q.H. Wang 3 , Meifeng Xu 1 , Stephen C. Woods 2 and Min Liu 1 1 Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA 2 Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH, USA 3 Department of Medicine, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA Correspondence to: Min Liu, email: lium@uc.edu Keywords: BDNF, TrkB receptor, estrogen, food intake, obesity Received: July 18, 2017 Accepted: August 31, 2017 Published: September 19, 2017 ABSTRACT Although compelling evidence indicates that estradiol (E2) acts in the nucleus tractus solitarius (NTS) to reduce food intake, the underlying mechanisms are largely unknown. We now report that estrogen’s anorectic action occurs through enhancing the strength of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase (TrkB) signaling in the NTS. Intra-4th-ventricular administration of a low dose of BDNF reduced food intake to a greater extent in ovariectomized (OVX) rats cyclically treated with E2 than in vehicle-treated OVX rats, implying that cyclic E2 replacement increases BDNF’s satiating potency. OVX significantly decreased bdnf gene expression in the NTS, and this was reversed by cyclic replacement of E2. Treatment of cultured primary neuronal cells from embryonic rat brainstem with E2 or PPT (ERα agonist), but not with DPN (ERβ agonist), significantly increased bdnf mRNA levels, indicating that ERα is the primary receptor mediating E2’s stimulatory effect on bdnf gene expression. Administration of the selective TrkB antagonist, ANA-12, directly into the NTS significantly attenuated E2-induced reductions of food intake and body weight gain in OVX rats, indicating that TrkB receptor activation is necessary for E2's anorectic effect. Finally, relative to controls, OVX mice with bdnf gene knockdown specifically in the NTS had a blunted feeding response to E2. These data collectively imply that BDNF/TrkB receptor signaling in the NTS is a downstream mediator of E2 in the control of energy intake.

Heterogeneous populations of hypothalamic neurons orchestrate energy balance via the release of specific signatures of neuropeptides. However, how specific intracellular machinery controls peptidergic identities and function of individual hypothalamic neuron’s remains largely unknown. The transcription factor T-box 3 (Tbx3) is expressed in hypothalamic neurons sensing and governing energy status, while human TBX3 haploinsufficiency has been linked with obesity. Here we demonstrate that loss-of-Tbx3 function in hypothalamic neurons causes weight gain and other metabolic disturbances by disrupting both peptidergic identity and plasticity of Pomc/Cart and Agrp/Npy neurons. These alterations are observed following loss of Tbx3 in both immature hypothalamic neurons and terminally differentiated murine neurons. We further establish the importance of Tbx3 for body weight regulation in Drosophila melanogaster and show that TBX3 is implicated in the differentiation of human embryonic stem cells (hESC) into hypothalamic Pomc neurons. Our data indicate that Tbx3 directs the terminal specification of neurons as functional components of the melanocortin system and is required for maintaining their peptidergic identity. In summary, we report the discovery of a mechanistic key process underlying the functional heterogeneity of hypothalamic neurons governing body weight and systemic metabolism.

Objective Recent decades have seen a marked increase in the prevalence of obesity and its associated comorbidities. This increase correlates with greater access to calorie-dense food that is often consumed later in the active phase of the day. Studies in high-fat diet-induced obese (DIO) mice indicate that restricting food access to their active (dark) phase is sufficient to reduce obesity. However, the specific mechanisms mediating these beneficial metabolic effects of dark restricted feeding (DRF) remain unknown. Methods We examined the impact of DRF on the response to peripheral signals regulating the central melanocortin system of DIO mice and on Mc4r−/− mice. Results The body weight loss following DRF has an acute onset that is sustained over time. This effect is contributed by a reduction on food intake that requires a functional central melanocortin system. Specifically, DRF impacts the circadian expression of melanocortin system genes in the arcuate nucleus of the hypothalamus (ARC). Consistent with this, DRF significantly increases the effectiveness of the fasting-feeding signals ghrelin and leptin that interact with the melanocortin system to regulate energy balance. Importantly, DRF did not reduce or prevent obesity in Mc4r−/− mice. Conclusions Taken together, our data reveal a critical role of brain melanocortin signaling in mediating the beneficial effects of timed feeding on metabolic control, supporting potential meaningful benefits in combining timed feeding with pharmacological targeting of the melanocortin signaling for the treatment of obesity.

Contrary to dogma, much physiological regulation utilizes learning from past experience to make responses that preemptively and effectively neutralize anticipated regulatory challenges. Understanding physiological regulation therefore requires expanding explanatory models beyond homeostasis and allostasis to emphasize the prominence of conditioning.

International audience; Astrocytes, microglia, and tanycytes play active roles in the regulation of hypothalamic feeding circuits. These non-neuronal cells are crucial in determining the functional interactions of specific neuronal subpopulations involved in the control of metabolism. Recent advances in biology, optics, genetics, and pharmacology have resulted in the emergence of novel and highly sophisticated approaches for studying hypothalamic neuronal-glial networks. Here we summarize the progress in the field and argue that glial-neuronal interactions provide a core hub integrating food-related cues, interoceptive signals, and internal states to adapt a complex set of physiological responses operating on different timescales to finely tune behavior and metabolism according to metabolic status. This expanding knowledge helps to redefine our understanding of the physiology of food intake and energy metabolism.

We previously found that 17β-estradiol (E2) stimulates apolipoprotein A-IV (apoA-IV) gene expression in the nucleus of the solitary tract (NTS) of lean ovariectomized (OVX) rodents. Here we report that in the NTS of high-fat diet-induced obese (DIO) rats, the apoA-IV mRNA level is significantly reduced and that the estrogenic effects on apoA-IV gene expression and food intake are impaired. E2 regulates apoA-IV gene expression through its nuclear receptor α (ERα), which requires co-activators, such as steroid receptor coactivator-1 (SRC-1), to facilitate the transcription of targeted genes. Interestingly, SRC-1 gene expression is significantly reduced in DIO OVX rats. SRC-1 is colocalized with apoA-IV in the cells of the NTS and E2 treatment enhances the recruitment of ERα and SRC-1 to the estrogen response element at the apoA-V promoter, implying the participation of SRC-1 in E2's stimulatory effect on apoA-IV gene expression. Using small hairpin RNA (shRNA), which was validated in cultured neuronal cells, we found that SRC-1 gene knockdown specifically in the NTS significantly diminished E2's anorectic action, leading to increased food intake and body weight. More importantly, the stimulatory effect of E2 on apoA-IV gene expression in the NTS was significantly attenuated in SRC-1 knockdown rats. These results collectively demonstrate the critical roles of NTS SRC-1 in mediating E2's actions on food intake and apoA-IV gene expression and suggest that reduced levels of endogenous SRC-1 and apoA-IV expression are responsible for the impaired E2's anorectic action in obese females.

Objective Roux-en-Y gastric bypass surgery (GB) is characterized by accentuated but short-lived postprandial elevations of blood glucose and insulin. This profile has been attributed to effects of relative hyperglycemia to directly stimulate β-cells and an augmented incretin effect. An additional glucose-independent stimulation of insulin secretion in GB subjects was hypothesized. Methods Fifteen subjects with prior GB, six matched obese non surgical controls, and seven lean individuals were recruited. Islet hormones were measured before and after meal ingestion during hyperinsulinemic hypoglycemic clamps to minimize the direct effects of glycemia and glucose-dependent gastrointestinal hormones on insulin secretion. Results The GB subjects had less suppression of fasting β-cell secretion during the insulin clamp compared to controls. In addition, meal-induced insulin secretion increased in the GB subjects but not controls during fixed sub-basal glycemia. In contrast, the glucagon responses to hypoglycemia and meal ingestion were lower in the GB subjects than controls. Conclusions Among subjects with GB, the response of insulin and glucagon secretion to decreasing blood glucose is blunted, but meal-induced insulin secretion is stimulated even at fixed systemic sub-basal glycemia. These findings indicate that, following GB, islet hormone secretion is altered as a result of factors beyond circulatory glucose levels.

Objective Melanocortin-4 receptors (MC4Rs) are highly expressed by dopamine-secreting neurons of the mesolimbic tract, but their functional role has not been fully resolved. Voluntary wheel running (VWR) induces adaptations in the mesolimbic dopamine system and has a myriad of long-term beneficial effects on health. In the present experiments we asked whether MC4R function regulates the effects of VWR, and whether VWR ameliorates MC4R-associated symptoms of the metabolic syndrome. Methods Electrically evoked dopamine release was measured in slice preparations from sedentary wild-type and MC4R-deficient Mc4rK314X (HOM) rats. VWR was assessed in wild-type and HOM rats, and in MC4R-deficient loxTBMc4r mice, wild-type mice body weight-matched to loxTBMc4r mice, and wild-type mice with intracerebroventricular administration of the MC4R antagonist SHU9119. Mesolimbic dopamine system function (gene/protein expression) and metabolic parameters were examined in wheel-running and sedentary wild-type and HOM rats. Results Sedentary obese HOM rats had increased electrically evoked dopamine release in several ventral tegmental area (VTA) projection sites compared to wild-type controls. MC4R loss-of-function decreased VWR, and this was partially independent of body weight. HOM wheel-runners had attenuated markers of intracellular D1-type dopamine receptor signaling despite increased dopamine flux in the VTA. VWR increased and decreased ΔFosB levels in the nucleus accumbens (NAc) of wild-type and HOM runners, respectively. VWR improved metabolic parameters in wild-type wheel-runners. Finally, moderate voluntary exercise corrected many aspects of the metabolic syndrome in HOM runners. Conclusions Central dopamine dysregulation during VWR reinforces the link between MC4R function and molecular and behavioral responding to rewards. The data also suggest that exercise can be a successful lifestyle intervention in MC4R-haploinsufficient individuals despite reduced positive reinforcement during exercise training., Highlights • MC4R-deficiency causes metabolic syndrome. • Loss of MC4R signaling decreases voluntary wheel running (VWR). • Despite moderate amounts of VWR, MC4R-associated metabolic syndrome is severely attenuated. • MC4R-deficiency is associated with mesolimbic dopamine dysregulation during VWR.

Background/Objectives Mounting evidence supports a link between circadian disruption and metabolic disease. Humans with circadian disruption (e.g., night-shift workers) have an increased risk of obesity and cardiometabolic diseases compared to the non-disrupted population. However, it is unclear if the obesity and obesity-related disorders associated with circadian disruption respond to therapeutic treatments as well as individuals with other types of obesity. Subjects/Methods Here, we test the effectiveness of the commonly used bariatric surgical procedure, Vertical Sleeve Gastrectomy (VSG) in mouse models of genetic and environmental circadian disruption. Results VSG led to a reduction in body weight and fat mass in both ClockΔ19 mutant and constant-light mouse models (P < .05), resulting in an overall metabolic improvement independent of circadian disruption. Interestingly, the decrease in body weight occurred without altering diurnal feeding or activity patterns (P > .05). Within circadian-disrupted models, VSG also led to improved glucose tolerance and lipid handling (P < .05). Conclusions Together these data demonstrate that VSG is an effective treatment for the obesity associated with circadian disruption, and that the potent effects of bariatric surgery are orthogonal to circadian biology. However, since the effects of bariatric surgery are independent of circadian disruption, VSG cannot be considered a cure for circadian disruption. These data have important implications for circadian-disrupted obese patients. Moreover, these results reveal new information about the metabolic pathways governing the effects of bariatric surgery as well as of circadian disruption.

Insulin detemir (DET) reduces glycemia comparably to other long-acting insulin formulations but causes less weight gain. Insulin signaling in the brain is catabolic, reducing food intake. We hypothesized that DET reduces weight gain, relative to other insulins, owing to increased transport into the central nervous system and/or increased catabolic action within the brain. Transport of DET and NPH insulin into the cerebrospinal fluid (CSF) was compared over several hours and after the administration of different doses peripherally in rats. DET and NPH had comparable saturable, receptor-mediated transport into the CSF. CSF insulin remained elevated significantly longer after intraperitoneal DET than after NPH. When administered acutely into the 3rd cerebral ventricle, both DET and NPH insulin reduced food intake and body weight at 24 h, and both food intake and body weight remained lower after DET than after NPH after 48 h. In direct comparison with another long-acting insulin, insulin glargine (GLAR), DET led to more prolonged increases in CSF insulin despite a shorter plasma half-life in both rats and mice. Additionally, peripheral DET administration reduced weight gain and increased CSF insulin compared with saline or GLAR in mice. Overall, these data support the hypothesis that DET has distinct effects on energy balance through enhanced and prolonged centrally mediated reduction of food intake.

In pancreatic β-cells, mitochondrial bioenergetics control glucose-stimulated insulin secretion. Mitochondrial dynamics are generally associated with quality control, maintaining the functionality of bioenergetics. By acute pharmacological inhibition of mitochondrial fission protein

Apolipoprotein AIV (ApoAIV) and cholecystokinin (CCK) are well-known satiating signals that are stimulated by fat consumption. Peripheral ApoAIV and CCK interact to prolong satiating signals. In the present study, we hypothesized that ApoAIV and CCK control energy homeostasis in response to high-fat diet feeding. To test this hypothesis, energy homeostasis in ApoAIV and CCK double knockout (ApoAIV/CCK-KO), ApoAIV knockout (ApoAIV-KO), and CCK knockout (CCK-KO) mice were monitored. When animals were maintained on a low-fat diet, ApoAIV/CCK-KO, ApoAIV-KO, and CCK-KO mice had comparable energy intake and expenditure, body weight, fat mass, fat absorption, and plasma parameters relative to the controls. In contrast, these KO mice exhibited impaired lipid transport to epididymal fat pads in response to intraduodenal infusion of dietary lipids. Furthermore, ApoAIV-KO mice had upregulated levels of CCK receptor 2 (CCK2R) in the small intestine while ApoAIV/CCK-KO mice had upregulated levels of CCK2R in the brown adipose tissue. After 20 wk of a high-fat diet, ApoAIV-KO and CCK-KO mice had comparable body weight and fat mass, as well as lower energy expenditure at some time points. However, ApoAIV/CCK-KO mice exhibited reduced body weight and adiposity relative to wild-type mice, despite having normal food intake. Furthermore, ApoAIV/CCK-KO mice displayed normal fat absorption and locomotor activity, as well as enhanced energy expenditure. These observations suggest that mice lacking ApoAIV and CCK have reduced body weight and adiposity, possibly due to impaired lipid transport and elevated energy expenditure.

Because human energy metabolism evolved to favor adiposity over leanness, the availability of palatable, easily attainable, and calorically dense foods has led to unprecedented levels of obesity and its associated metabolic co-morbidities that appear resistant to traditional lifestyle interventions. However, recent progress identifying the molecular signaling pathways through which the brain and the gastrointestinal system communicate to govern energy homeostasis, combined with emerging insights on the molecular mechanisms underlying successful bariatric surgery, gives reason to be optimistic that novel precision medicines that mimic, enhance, and/or modulate gut-brain signaling can have unprecedented potential for stopping the obesity and type 2 diabetes pandemics.

Adaptive thermogenesis is the process of heat generation in response to cold stimulation. It is under the control of the sympathetic nervous system, whose chief effector is the catecholamine norepinephrine (NE). NE enhances thermogenesis through β3-adrenergic receptors to activate brown adipose tissue and by 'browning' white adipose tissue. Recent studies have reported that alternative activation of macrophages in response to interleukin (IL)-4 stimulation induces the expression of tyrosine hydroxylase (TH), a key enzyme in the catecholamine synthesis pathway, and that this activation provides an alternative source of locally produced catecholamines during the thermogenic process. Here we report that the deletion of Th in hematopoietic cells of adult mice neither alters energy expenditure upon cold exposure nor reduces browning in inguinal adipose tissue. Bone marrow-derived macrophages did not release NE in response to stimulation with IL-4, and conditioned media from IL-4-stimulated macrophages failed to induce expression of thermogenic genes, such as uncoupling protein 1 (Ucp1), in adipocytes cultured with the conditioned media. Furthermore, chronic treatment with IL-4 failed to increase energy expenditure in wild-type, Ucp1(-/-) and interleukin-4 receptor-α double-negative (Il4ra(-/-)) mice. In agreement with these findings, adipose-tissue-resident macrophages did not express TH. Thus, we conclude that alternatively activated macrophages do not synthesize relevant amounts of catecholamines, and hence, are not likely to have a direct role in adipocyte metabolism or adaptive thermogenesis.

International audience; Neuronal circuits in the brain help to control feeding behavior and systemic metabolism in response to afferent nutrient and hormonal signals. Although astrocytes have historically been assumed to have little relevance for such neuroendocrine control, we investigated whether lipid uptake via lipoprotein lipase (LPL) in astrocytes is required to centrally regulate energy homeostasis. Ex vivo studies with hypothalamus-derived astrocytes showed that LPL expression is upregulated by oleic acid, whereas it is decreased in response to palmitic acid or triglycerides. Likewise, astrocytic LPL deletion reduced the accumulation of lipid droplets in those glial cells. Consecutive in vivo studies showed that postnatal ablation of LPL in glial fibrillary acidic protein-expressing astrocytes induced exaggerated body weight gain and glucose intolerance in mice exposed to a high-fat diet. Intriguingly, astrocytic LPL deficiency also triggered increased ceramide content in the hypothalamus, which may contribute to hypothalamic insulin resistance. We conclude that hypothalamic LPL functions in astrocytes to ensure appropriately balanced nutrient sensing, ceramide distribution, body weight regulation, and glucose metabolism.

In pancreatic β-cells, mitochondrial bioenergetics control glucose-stimulated insulin secretion. Mitochondrial dynamics are generally associated with quality control, maintaining the functionality of bioenergetics. By acute pharmacological inhibition of mitochondrial fission protein Drp1, we demonstrate in this study that mitochondrial fission is necessary for glucose-stimulated insulin secretion in mouse and human islets. We confirm that genetic silencing of Drp1 increases mitochondrial proton leak in MIN6 cells. However, our comprehensive analysis of pancreatic islet bioenergetics reveals that Drp1 does not control insulin secretion via its effect on proton leak but instead via modulation of glucose-fueled respiration. Notably, pyruvate fully rescues the impaired insulin secretion of fission-deficient β-cells, demonstrating that defective mitochondrial dynamics solely affect substrate supply upstream of oxidative phosphorylation. The present findings provide novel insights into how mitochondrial dysfunction may cause pancreatic β-cell failure. In addition, the results will stimulate new thinking in the intersecting fields of mitochondrial dynamics and bioenergetics, as treatment of defective dynamics in mitochondrial diseases appears to be possible by improving metabolism upstream of mitochondria.

Consuming a calorically dense diet stimulates microglial reactivity in the mediobasal hypothalamus (MBH) in association with decreased number of appetite-curbing pro-opiomelanocortin (POMC) neurons; whether the reduction in POMC neuronal function is secondary to the microglial activation is unclear. Here we show that in hypercaloric diet-induced obese mice, persistently activated microglia in the MBH hypersecrete TNFα that in turn stimulate mitochondrial ATP production in POMC neurons, promoting mitochondrial fusion in their neurites, and increasing POMC neuronal firing rates and excitability. Specific disruption of the gene expressions of TNFα downstream signals TNFSF11A or NDUFAB1 in the MBH of diet-induced obese mice reverses mitochondrial elongation and reduces obesity. These data imply that in a hypercaloric environment, persistent elevation of microglial reactivity and consequent TNFα secretion induces mitochondrial stress in POMC neurons that contributes to the development of obesity., Long-term consumption of a calorie-rich diet persistently activates brain microglia. Here, the authors show that microglial activity in mouse brains oscillates daily in conjunction with feeding, and that TNFα, secreted by activated microglia, induces mitochondrial stress in satiety-promoting POMC neurons.

Meal-fed (MF) rats with access to food for only 4 consecutive hours during the light cycle learn to eat large meals to maintain energy balance. MF animals develop behavioral and endocrine changes that permit glucose tolerance despite increased meal size. We hypothesized that enhanced activity of the enteroinsular axis mediates glucose homeostasis during MF. Cohorts of rats were allocated to MF or ad libitum (AL) regimens for 2–4 wk. Insulin secretion and glucose tolerance were determined after oral carbohydrate and intraperitoneal (ip) and intravenous (iv) glucose. MF rats ate less than AL in the first week but maintained a comparable weight trajectory thereafter. MF rats had decreased glucose excursions after a liquid mixed meal (AUC: MF 75 ± 7, AL 461 ± 28 mmol·l−1·min, P < 0.001), with left-shifted insulin secretion (AUC0–15: MF 31.0 ± 4.9, AL 9.6 ± 4.4 pM·min, P < 0.02), which peaked before a significant rise in blood glucose. Both groups had comparable fasting glucagon levels, but postprandial responses were lower with MF. However, neither intestinal expression of proGIP and proglucagon mRNA nor plasma incretin levels differed between MF and AL groups. There were no differences in the insulin response to ip or iv glucose between MF and AL rats. These findings demonstrate that MF improves oral glucose tolerance and is associated with significant changes in postprandial islet hormone secretion. Because MF enhanced β-cell function during oral but not parenteral carbohydrate administration, and was not accounted for by changes in circulating incretins, these results support a neural mechanism of adaptive insulin secretion.

We asked whether chronic tolerance and the hyperthermic sign-reversal induced by repeated 60% N2O exposures could be extinguished using a cue-exposure paradigm. Rats received 18 N2O administrations in a total calorimetry system that simultaneously measures core temperature (Tc), metabolic heat production (HP), and body heat loss (HL). Each exposure entailed a 2-h baseline period followed by a 1.5-h N2O exposure. The 18 drug exposures induced a robust intra-administration hyperthermia in which the initial hypothermic effect of N2O inverted to a significant hyperthermic sign-reversal during N2O inhalation due primarily to an acquired robust increase in HP. The rats were then randomized to one of three extinction procedures (n=8/procedure) over a 20-d interval: 1) a N2O-abstinent home-cage group (HC) that received only the usual animal care; 2) a cue-exposure group (CEXP) in which the animals were placed in the calorimeter 8 times but received no N2O; and 3) a drug-onset-cue group (DOC) in which animals received a brief N2O exposure in the calorimeter that mimicked the first 3 min of an actual 60% N2O trial. Following the extinction sessions, all rats received a 60% N2O test trial and Tc, HP and HL were assessed. The hyperthermic sign-reversal remained fully intact during the test trial, with no significant differences observed among groups in any post-baseline change in any thermal outcome. These data suggest that cue exposure may not be an efficacious strategy to reduce sign-reversals that develop with chronic drug use.

Uroguanylin is a gastrointestinal hormone primarily involved in fluid and electrolyte handling. It has recently been reported that prouroguanylin, secreted postprandially, is converted to uroguanylin in the brain and activates the receptor guanylate cyclase-C (GC-C) to reduce food intake and prevent obesity. We tested central nervous system administration of two GC-C agonists and found no significant reduction of food intake. We also carefully phenotyped mice lacking the GC-C receptor and found them to have normal body weight, adiposity, and glucose tolerance. Interestingly, uroguanylin knockout mice had a small but significant increase in body weight and adiposity that was accompanied by glucose intolerance. Our data indicate that the modest effects of uroguanylin on energy and glucose homeostasis are not mediated by central GC-C receptors.

Initial administration of 60% nitrous oxide (N2O) at 21°C ambient temperature (Ta) reduces core temperature (Tc) in rats, but tolerance develops to this hypothermic effect over several administrations. After additional N2O administrations, a hyperthermic overcompensation (sign-reversal) develops such that Tc exceeds control levels during N2O inhalation. This study investigated whether rats would employ behavioral thermoregulation to facilitate, or oppose, a previously acquired hyperthermic overcompensation during N2O administration. To establish a hyperthermic sign-reversal, male Long-Evans rats (N=12) received ten 3-h administrations of 60% N2O while housed in a gas-tight, live-in, "inactive" thermal gradient (~21°C). Following the tenth N2O exposure, the thermal gradient was activated (range of 10-37°C), and rats received both a control gas session and a 60% N2O test session in counterbalanced order. Mean Tc during N2O inhalation in the inactive gradient was reliably hypothermic during the first exposure but was reliably hyperthermic by the tenth exposure. When subsequently exposed to 60% N2O in the active gradient, rats selected a cooler Ta, which blunted the hyperthermic sign-reversal and lowered Tc throughout the remainder of the N2O exposure. Thus, autonomic heat production effectors mediating the hyperthermia were opposed by a behavioral effector that promoted increased heat loss via selection of a cooler ambient temperature. These data are compatible with an allostatic model of drug addiction that suggests that dysregulatory overcompensation in the drugged-state may motivate behaviors (e.g., drug taking) that oppose the overcompensation, thereby creating a vicious cycle of escalating drug consumption and recurring dysregulation.

Although estrogens have been implicated in the regulation of apolipoprotein A-IV (apo A-IV) gene expression in the nucleus tractus solitarius, previous studies have not defined the molecular mechanism. The aim of this study was to examine the transcriptional mechanisms involved in regulation of apo A-IV gene expression. Using cultured primary neuronal cells from rat embryonic brainstems, we found that treatment with 10nM 17β-estradiol-3-benzoate (E2) or 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (an estrogen receptor [ER]α agonist), but not 2,3-bis(4-hydroxyphenyl)-propionitrile (an ERβ agonist), significantly increased apo A-IV gene expression, compared with vehicle treatment. This effect of E2 was abolished when the cells were incubated with E2 linked to BSA, which prevents E2 from entering cells, implying that a nongenomic mechanism of E2 is not involved. Two putative estrogen response elements were identified at the 5′-upstream region of the apo A-IV gene promoter, but only 1 of them was able to recruit ERα, leading to increased apo A-IV gene expression, as determined by chromatin immunoprecipitation assay and luciferase activity analysis. A cyclic regimen of E2 or 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol treatment for 8 cycles (4 d/cycle, mimicking the ovarian cycle of female rats) in ovariectomized female rats significantly reduced food intake and body weight gain and increased apo A-IV gene expression in the nucleus tractus solitarius, relative to vehicle. These data collectively demonstrate that nuclear ERα is the primary mediator of E2's action on apo A-IV gene expression and suggest that increased signaling of endogenous apo A-IV may at least partially mediate E2-induced inhibitory effect on feeding.

Behavioral modifications for the treatment of obesity, including caloric restriction, have notoriously low long-term success rates relative to bariatric weight-loss surgery. The reasons for the difference in sustained weight loss are not clear. One possibility is that caloric restriction alone activates the stress-responsive hypothalamo-pituitary-adrenocortical (HPA) axis, undermining the long-term maintenance of weight loss, and that this is abrogated after bariatric surgery. Accordingly, we compared the HPA response to weight loss in five groups of male rats: (1) high-fat diet-induced obese (DIO) rats treated with Roux-en-Y gastric bypass surgery (RYGB, n = 7), (2) DIO rats treated with vertical sleeve gastrectomy (VSG, n = 11), (3) DIO rats given sham surgery and subsequently restricted to the food intake of the VSG/RYGB groups (Pair-fed, n = 11), (4) ad libitum-fed DIO rats given sham surgery (Obese, n = 11) and (5) ad libitum chow-fed rats given sham surgery (Lean, n = 12). Compared with Lean...

Homeostasis, the dominant explanatory framework for physiological regulation, has undergone significant revision in recent years, with contemporary models differing significantly from the original formulation. Allostasis, an alternative view of physiological regulation, goes beyond its homeostatic roots, offering novel insights relevant to our understanding and treatment of several chronic health conditions. Despite growing enthusiasm for allostasis, the concept remains diffuse, due in part to ambiguity as to how the term is understood and used, impeding meaningful translational and clinical research on allostasis. Here, we provide a more focused understanding of homeostasis and allostasis by explaining how both play a role in physiological regulation, and a critical analysis of regulation suggests how homeostasis and allostasis can be distinguished. Rather than focusing on changes in the value of a regulated variable (e.g., body temperature, body adiposity, or reward), research investigating the activity and relationship among the multiple regulatory loops that influence the value of these regulated variables may be the key to distinguishing homeostasis and allostasis. The mechanisms underlying physiological regulation and dysregulation are likely to have important implications for health and disease.

A feedback system for the regulation of food intake and body weight, consisting of two elements is proposed. One is related to the quantitiy and quality of the food ingested. It consists of neural afferents, psychosocial conditioning factors, and peptide signals from the gastrointestinal tract released by specific nutrient intake. The other is also sensitive to nutrient intake, but importantly modulated by relative adiposity. We present evidence to suggest that insulin serves as the key feedback signal to the central nervous system to serve this second function (body adiposity signal). Insulin has been found in cerebrospinal fluid where its concentration is increased by systemic infusions of glucose or insulin and is proportional to its concentration in plasma. When insulin (10 and 100 μU/kg/day) is infused into the lateral cerebral ventricles of free feeding baboons a dose dependent suppression of food intake and body weight is found. Intravenous infusion of 25% and 50% of total calories as glucose elevates endogenous insulin concentrations and suppresses food intake. These findings suggest that the amount of insulin secreted per day and more modulates food intake to maintain a constant body weight.

Obesity-induced metabolic dysfunctions increase the risk for vascular diseases, including type II diabetes and stroke. Managing obesity is of interest to address the worldwide health problem; however, the role of genetic variability in human obesity development and specific targets for obesity-related metabolic disease have not been thoroughly studied. A SNP in the brain-derived neurotropic factor (BDNF) gene that results in the substitution of a valine with a methionine at codon 66 (Val66Met) occurs with a high frequency in humans. This study addressed the effect of genetic variability in developing obesity and the efficacy of the inhibition of cluster of differentiation 36 (CD36), a multifunctional receptor implicated in obesity and insulin resistance, in WT mice and mice with the BDNF Val66Met variant. CD36 inhibition by salvionolic acid B (SAB) in diet-induced obese WT mice reduced visceral fat accumulation and improved insulin resistance. The benefit of SAB was abrogated in CD36 knockout mice, showing the specificity of SAB. In addition, mice with the Val66Met variant in both alleles (BDNFM/M) fed a high-fat diet exhibited extreme obesity with increased CD36 gene and protein levels in macrophages. Chronic SAB treatment in BDNFM/M mice significantly decreased visceral fat accumulation and improved insulin resistance. Notably, the effect of SAB was greater in the extremely obese BDNFM/M mice compared with the WT mice. The study demonstrated a link between BDNF Val66Met and elevated CD36 expression and suggested that CD36 inhibition may be a potential strategy to improve metabolic dysfunctions and to normalize risk factors for vascular diseases in the obese population.

In the article listed above, ERX was erroneously omitted from the duality of interest for Matthias H. …

The melanocortin system is a brain circuit that influences energy balance by regulating energy intake and expenditure. In addition, the brain-melanocortin system controls adipose tissue metabolism to optimize fuel mobilization and storage. Specifically, increased brain-melanocortin signaling or negative energy balance promotes lipid mobilization by increasing sympathetic nervous system input to adipose tissue. In contrast, calorie-independent mechanisms favoring energy storage are less understood. Here, we demonstrate that reduction of brain-melanocortin signaling actively promotes fat mass gain by activating the lipogenic program and adipocyte and endothelial cell proliferation in white fat depots independently of caloric intake via efferent nerve fibers conveyed by the common hepatic branch of the vagus nerve. Those vagally regulated obesogenic signals also contribute to the fat mass gain following chronic high-fat diet feeding. These data reveal a physiological mechanism whereby the brain controls energy stores that may contribute to increased susceptibility to obesity., Cell Reports, 27 (8), ISSN:2666-3864, ISSN:2211-1247