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Metabolic diseases such as obesity and type 2 diabetes are marked by insulin resistance 1,2 . Cells within the arcuate nucleus of the hypothalamus (ARC), which are crucial for regulating metabolism, become insulin resistant during the progression of metabolic disease 3-8 , but these mechanisms are not fully understood. Here we investigated the role of a specialized chondroitin sulfate proteoglycan extracellular matrix, termed a perineuronal net, which surrounds ARC neurons. In metabolic disease, the perineuronal net of the ARC becomes augmented and remodelled, driving insulin resistance and metabolic dysfunction. Disruption of the perineuronal net in obese mice, either enzymatically or with small molecules, improves insulin access to the brain, reversing neuronal insulin resistance and enhancing metabolic health. Our findings identify ARC extracellular matrix remodelling as a fundamental mechanism driving metabolic diseases., (© 2024. The Author(s).)

Glucagon-like peptide receptor (GLP-1R) agonists (e.g., semaglutide, liraglutide, etc.) are efficient treatment options for people with type 2 diabetes and obesity. The manufacturing method to produce semaglutide, a blockbuster GLP-1 drug on the market, involves multistep synthesis. The large peptide has a hydrophobic fatty acid side chain that makes it sparingly soluble, and its handling, purification, and large-scale production difficult. The growing demand for semaglutide that the manufacturer is not capable of addressing immediately triggered a worldwide shortage. Thus, we have developed a potential alternative analogue to semaglutide by replacing the hydrophobic fatty acid with a hydrophilic human complex-type biantennary oligosaccharide. Our novel glycoGLP-1 analogue was isolated in an ∼10-fold higher yield compared with semaglutide. Importantly, our glycoGLP-1 analogue possessed a similar GLP-1R activation potency to semaglutide and was biologically active in vivo in reducing glucose levels to a similar degree as semaglutide.

Small extracellular vesicles (EVs) are signalling messengers that regulate inter-tissue communication through delivery of their molecular cargo. Here, we show that liver-derived EVs are acute regulators of whole-body glycaemic control in mice. Liver EV secretion into the circulation is increased in response to hyperglycaemia, resulting in increased glucose effectiveness and insulin secretion through direct inter-organ EV signalling to skeletal muscle and the pancreas, respectively. This acute blood glucose lowering effect occurs in healthy and obese mice with non-alcoholic fatty liver disease, despite marked remodelling of the liver-derived EV proteome in obese mice. The EV-mediated blood glucose lowering effects were recapitulated by administration of liver EVs derived from humans with or without progressive non-alcoholic fatty liver disease, suggesting broad functional conservation of liver EV signalling and potential therapeutic utility. Taken together, this work reveals a mechanism whereby liver EVs act on peripheral tissues via endocrine signalling to restore euglycaemia in the postprandial state., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Nutrients can impact and regulate cellular metabolism and cell function which is particularly important for the activation and function of diverse immune subsets. Among the critical nutrients for immune cell function and fate, glutamine is possibly the most widely recognised immunonutrient, playing key roles in TCA cycle, heat shock protein responses and antioxidant systems. In addition, glutamine is also involved with inter-organ ammonia transport, and this is particularly important for not only immune cells, but also to the brain, especially in catabolic situations such as critical care and extenuating exercise. The well characterised fall in blood glutamine availability has been the main reason for studies to investigate the possible effects of glutamine replacement via supplementation but many of the results are in poor agreement. At the same time, a range of complex pathways involved in glutamine metabolism have been revealed via supplementation studies. This article will briefly review the function of glutamine in the immune system, with emphasis on metabolic mechanisms, and the emerging role of glutamine in the brain glutamate/gamma-amino butyric acid cycle. In addition, relevant aspects of glutamine supplementation are discussed.

Exercise induces signaling networks to improve muscle function and confer health benefits. To identify divergent and common signaling networks during and after different exercise modalities, we performed a phosphoproteomic analysis of human skeletal muscle from a cross-over intervention of endurance, sprint, and resistance exercise. This identified 5,486 phosphosites regulated during or after at least one type of exercise modality and only 420 core phosphosites common to all exercise. One of these core phosphosites was S67 on the uncharacterized protein C18ORF25, which we validated as an AMPK substrate. Mice lacking C18ORF25 have reduced skeletal muscle fiber size, exercise capacity, and muscle contractile function, and this was associated with reduced phosphorylation of contractile and Ca 2+ handling proteins. Expression of C18ORF25 S66/67D phospho-mimetic reversed the decreased muscle force production. This work defines the divergent and canonical exercise phosphoproteome across different modalities and identifies C18ORF25 as a regulator of exercise signaling and muscle function., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.

Insulin signals to the brain where it coordinates multiple physiological processes underlying energy and glucose homeostasis. This review explores where and how insulin interacts within the brain parenchyma, how brain insulin signalling functions to coordinate energy and glucose homeostasis and how this contributes to the pathogenesis of metabolic disease., (© 2021 British Society for Neuroendocrinology.)

The importance of hypothalamic insulin signaling on feeding and glucose metabolism remains unclear. We report that insulin acts on AgRP neurons to acutely decrease meal size and thereby limit postprandial glucose and insulin excursions. The promotion of insulin signaling in AgRP neurons decreased meal size without altering total caloric intake, whereas the genetic ablation of the insulin receptor had the opposite effect. The promotion of insulin signaling also decreased the intake of sucrose-sweetened water or high-fat food over standard chow, without influencing food-seeking and hedonic behaviors. The ability of heightened insulin signaling to override the hedonistic consumption of highly palatable high-fat food attenuated the development of systemic insulin resistance, without affecting body weight. Our findings define an unprecedented mechanism by which insulin acutely influences glucose metabolism. Approaches that enhance insulin signaling in AgRP neurons may provide a means for altering feeding behavior in a nutrient-dense environment to combat the metabolic syndrome., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

The cytokine, GDF15, is produced in pathological states which cause cellular stress, including cancer. When over expressed, it causes dramatic weight reduction, suggesting a role in disease-related anorexia. Here, we demonstrate that the GDF15 receptor, GFRAL, is located in a subset of cholecystokinin neurons which span the area postrema and the nucleus of the tractus solitarius of the mouse. GDF15 activates GFRAL AP/NTS neurons and supports conditioned taste and place aversions, while the anorexia it causes can be blocked by a monoclonal antibody directed at GFRAL or by disrupting CCK neuronal signalling. The cancer-therapeutic drug, cisplatin, induces the release of GDF15 and activates GFRAL AP/NTS neurons, as well as causing significant reductions in food intake and body weight in mice. These metabolic effects of cisplatin are abolished by pre-treatment with the GFRAL monoclonal antibody. Our results suggest that GFRAL neutralising antibodies or antagonists may provide a co-treatment opportunity for patients undergoing chemotherapy., Competing Interests: AW, RS, KT, CF, GD, GD, FR, FG No competing interests declared, EB, JD, JA, DS, TC, PE Paid employee of Eli Lilly. SL BB/S008098/1 is a BBSRC Industrial Partnership Award between SML and Eli Lilly, (© 2020, Worth et al.)

Objectives: Nutrient sensing by hypothalamic neurons is critical for the regulation of food intake and energy expenditure. We aimed to identify long- and medium-chain fatty acid species transported into the brain, their effects on energy balance, and the mechanisms by which they regulate activity of hypothalamic neurons., Methods: Simultaneous blood and cerebrospinal fluid (CSF) sampling was undertaken in rats and metabolic analyses using radiolabeled fatty acid tracers were performed on mice. Electrophysiological recording techniques were used to investigate signaling mechanisms underlying fatty acid-induced changes in activity of pro-opiomelanocortin (POMC) neurons., Results: Medium-chain fatty acid (MCFA) octanoic acid (C8:0), unlike long-chain fatty acids, was rapidly transported into the hypothalamus of mice and almost exclusively oxidized, causing rapid, transient reductions in food intake and increased energy expenditure. Octanoic acid differentially regulates the excitability of POMC neurons, activating these neurons directly via GPR40 and inducing inhibition via an indirect non-synaptic, purine, and adenosine receptor-dependent mechanism., Conclusions: MCFA octanoic acid is a central signaling nutrient that targets POMC neurons via distinct direct and indirect signal transduction pathways to instigate changes in energy status. These results could explain the beneficial health effects that accompany MCFA consumption., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Although adoptive T-cell therapy has shown remarkable clinical efficacy in haematological malignancies, its success in combating solid tumours has been limited. Here, we report that PTPN2 deletion in T cells enhances cancer immunosurveillance and the efficacy of adoptively transferred tumour-specific T cells. T-cell-specific PTPN2 deficiency prevented tumours forming in aged mice heterozygous for the tumour suppressor p53. Adoptive transfer of PTPN2-deficient CD8 + T cells markedly repressed tumour formation in mice bearing mammary tumours. Moreover, PTPN2 deletion in T cells expressing a chimeric antigen receptor (CAR) specific for the oncoprotein HER-2 increased the activation of the Src family kinase LCK and cytokine-induced STAT-5 signalling, thereby enhancing both CAR T-cell activation and homing to CXCL9/10-expressing tumours to eradicate HER-2 + mammary tumours in vivo. Our findings define PTPN2 as a target for bolstering T-cell-mediated anti-tumour immunity and CAR T-cell therapy against solid tumours., (© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)

The importance of hypothalamic leptin and insulin resistance in the development and maintenance of obesity remains unclear. The tyrosine phosphatases protein tyrosine phosphatase 1B (PTP1B) and T cell protein tyrosine phosphatase (TCPTP) attenuate leptin and insulin signaling and are elevated in the hypothalami of obese mice. We report that elevated PTP1B and TCPTP antagonize hypothalamic leptin and insulin signaling and contribute to the maintenance of obesity. Deletion of PTP1B and TCPTP in the hypothalami of obese mice enhances CNS leptin and insulin sensitivity, represses feeding, and increases browning, to decrease adiposity and improve glucose metabolism. The daily intranasal administration of a PTP1B inhibitor, plus the glucocorticoid antagonist RU486 that decreases TCPTP expression, represses feeding, increases browning, promotes weight loss, and improves glucose metabolism in obese mice. Our findings causally link heightened hypothalamic PTP1B and TCPTP with leptin and insulin resistance and the maintenance of obesity and define a viable pharmacological approach by which to promote weight loss in obesity., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Insulin action in the hypothalamus results in the suppression of hepatic glucose production (HGP). Obesity is often associated with a diminished response to insulin, leading to impaired suppression of HGP in obese mice. Here, we demonstrate that blocking central leptin signaling in diet-induced obese (DIO) mice restores the liver's ability to suppress glucose production. Leptin increases the expression of the insulin receptor phosphatase PTP1B, which is highly expressed in the hypothalamus of DIO mice. We demonstrate that the central pharmacological inhibition or ARH-targeted deletion of PTP1B restores the suppression of HGP in obese mice. Additionally, mice that lack PTP1B in AgRP neurons exhibit enhanced ARH insulin signaling and have improved glucose tolerance and insulin sensitivity. Overall, our findings indicate that obesity-induced increases in PTP1B diminish insulin action in the hypothalamus, resulting in unconstrained HGP and contributing to hyperglycemia in obesity., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Celastrol is a natural pentacyclic triterpene used in traditional Chinese medicine with significant weight-lowering effects. Celastrol-administered mice at 100 μg/kg decrease food consumption and body weight via a leptin-dependent mechanism, yet its molecular targets in this pathway remain elusive. Here, we demonstrate in vivo that celastrol-induced weight loss is largely mediated by the inhibition of leptin negative regulators protein tyrosine phosphatase (PTP) 1B (PTP1B) and T-cell PTP (TCPTP) in the arcuate nucleus (ARC) of the hypothalamus. We show in vitro that celastrol binds reversibly and inhibits noncompetitively PTP1B and TCPTP. NMR data map the binding site to an allosteric site in the catalytic domain that is in proximity of the active site. By using a panel of PTPs implicated in hypothalamic leptin signaling, we show that celastrol additionally inhibited PTEN and SHP2 but had no activity toward other phosphatases of the PTP family. These results suggest that PTP1B and TCPTP in the ARC are essential for celastrol's weight lowering effects in adult obese mice.

Obesity is a major driver of cancer, especially hepatocellular carcinoma (HCC). The prevailing view is that non-alcoholic steatohepatitis (NASH) and fibrosis or cirrhosis are required for HCC in obesity. Here, we report that NASH and fibrosis and HCC in obesity can be dissociated. We show that the oxidative hepatic environment in obesity inactivates the STAT-1 and STAT-3 phosphatase T cell protein tyrosine phosphatase (TCPTP) and increases STAT-1 and STAT-3 signaling. TCPTP deletion in hepatocytes promoted T cell recruitment and ensuing NASH and fibrosis as well as HCC in obese C57BL/6 mice that normally do not develop NASH and fibrosis or HCC. Attenuating the enhanced STAT-1 signaling prevented T cell recruitment and NASH and fibrosis but did not prevent HCC. By contrast, correcting STAT-3 signaling prevented HCC without affecting NASH and fibrosis. TCPTP-deletion in hepatocytes also markedly accelerated HCC in mice treated with a chemical carcinogen that promotes HCC without NASH and fibrosis. Our studies reveal how obesity-associated hepatic oxidative stress can independently contribute to the pathogenesis of NASH, fibrosis, and HCC., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Hypothalamic neurons respond to nutritional cues by altering gene expression and neuronal excitability. The mechanisms that control such adaptive processes remain unclear. Here we define populations of POMC neurons in mice that are activated or inhibited by insulin and thereby repress or inhibit hepatic glucose production (HGP). The proportion of POMC neurons activated by insulin was dependent on the regulation of insulin receptor signaling by the phosphatase TCPTP, which is increased by fasting, degraded after feeding and elevated in diet-induced obesity. TCPTP-deficiency enhanced insulin signaling and the proportion of POMC neurons activated by insulin to repress HGP. Elevated TCPTP in POMC neurons in obesity and/or after fasting repressed insulin signaling, the activation of POMC neurons by insulin and the insulin-induced and POMC-mediated repression of HGP. Our findings define a molecular mechanism for integrating POMC neural responses with feeding to control glucose metabolism., Competing Interests: GD, NM, RL, SM, JP, AM, SS, JB, ZZ, MC, SA, TH, DS, TT No competing interests declared, (© 2018, Dodd et al.)

Insulin regulates glucose metabolism by eliciting effects on peripheral tissues as well as the brain. Insulin receptor (IR) signaling inhibits AgRP-expressing neurons in the hypothalamus to contribute to the suppression of hepatic glucose production (HGP) by insulin, whereas AgRP neuronal activation attenuates brown adipose tissue (BAT) glucose uptake. The tyrosine phosphatase TCPTP suppresses IR signaling in AgRP neurons. Hypothalamic TCPTP is induced by fasting and degraded after feeding. Here we assessed the influence of TCPTP in AgRP neurons in the control of glucose metabolism. TCPTP deletion in AgRP neurons ( Agrp -Cre; Ptpn2 fl/fl ) enhanced insulin sensitivity, as assessed by the increased glucose infusion rates, and reduced HGP during hyperinsulinemic-euglycemic clamps, accompanied by increased [ 14 C]-2-deoxy-d-glucose uptake in BAT and browned white adipose tissue. TCPTP deficiency in AgRP neurons promoted the intracerebroventricular insulin-induced repression of hepatic gluconeogenesis in otherwise unresponsive food-restricted mice, yet had no effect in fed/satiated mice where hypothalamic TCPTP levels are reduced. The improvement in glucose homeostasis in Agrp -Cre; Ptpn2 fl/fl mice was corrected by IR heterozygosity ( Agrp -Cre; Ptpn2 fl/fl ; Insr fl/+ ), causally linking the effects on glucose metabolism with the IR signaling in AgRP neurons. Our findings demonstrate that TCPTP controls IR signaling in AgRP neurons to coordinate HGP and brown/beige adipocyte glucose uptake in response to feeding/fasting., (© 2018 by the American Diabetes Association.)

A growing body of evidence from research in rodents and humans has identified insulin as an important neuoregulatory peptide in the brain, where it coordinates diverse aspects of energy balance and peripheral glucose homeostasis. This review discusses where and how insulin interacts within the brain and evaluates the physiological and pathophysiological consequences of central insulin signalling in metabolism, obesity and type 2 diabetes., (© 2017 British Society for Neuroendocrinology.)

In the thymus, hematopoietic progenitors commit to the T cell lineage and undergo sequential differentiation to generate diverse T cell subsets, including major histocompatibility complex (MHC)-restricted αβ T cell receptor (TCR) T cells and non-MHC-restricted γδ TCR T cells. The factors controlling precursor commitment and their subsequent maturation and specification into αβ TCR versus γδ TCR T cells remain unclear. Here, we show that the tyrosine phosphatase PTPN2 attenuates STAT5 (signal transducer and activator of transcription 5) signaling to regulate T cell lineage commitment and SRC family kinase LCK and STAT5 signaling to regulate αβ TCR versus γδ TCR T cell development. Our findings identify PTPN2 as an important regulator of critical checkpoints that dictate the commitment of multipotent precursors to the T cell lineage and their subsequent maturation into αβ TCR or γδ TCR T cells., (© 2017 Wiede et al.)

Aims/hypothesis: In obesity oxidative stress is thought to contribute to the development of insulin resistance, non-alcoholic fatty liver disease and the progression to non-alcoholic steatohepatitis. Our aim was to examine the precise contributions of hepatocyte-derived H 2 O 2 to liver pathophysiology., Methods: Glutathione peroxidase (GPX) 1 is an antioxidant enzyme that is abundant in the liver and converts H 2 O 2 to water. We generated Gpx1 lox/lox mice to conditionally delete Gpx1 in hepatocytes (Alb-Cre;Gpx1 lox/lox ) and characterised mice fed chow, high-fat or choline-deficient amino-acid-defined (CDAA) diets., Results: Chow-fed Alb-Cre;Gpx1 lox/lox mice did not exhibit any alterations in body composition or energy expenditure, but had improved insulin sensitivity and reduced fasting blood glucose. This was accompanied by decreased gluconeogenic and increased glycolytic gene expression as well as increased hepatic glycogen. Hepatic insulin receptor Y1163/Y1163 phosphorylation and Akt Ser-473 phosphorylation were increased in fasted chow-fed Alb-Cre;Gpx1 lox/lox mice, associated with increased H 2 O 2 production and insulin signalling in isolated hepatocytes. The enhanced insulin signalling was accompanied by the increased oxidation of hepatic protein tyrosine phosphatases previously implicated in the attenuation of insulin signalling. High-fat-fed Alb-Cre;Gpx1 lox/lox mice did not exhibit alterations in weight gain or hepatosteatosis, but exhibited decreased hepatic inflammation, decreased gluconeogenic gene expression and increased insulin signalling in the liver. Alb-Cre;Gpx1 lox/lox mice fed a CDAA diet that promotes non-alcoholic steatohepatitis exhibited decreased hepatic lymphocytic infiltrates, inflammation and liver fibrosis., Conclusions/interpretation: Increased hepatocyte-derived H 2 O 2 enhances hepatic insulin signalling, improves glucose control and protects mice from the development of non-alcoholic steatohepatitis.

The hypothalamus is critical to the coordination of energy balance and glucose homeostasis. It responds to peripheral factors, such as insulin and leptin, that convey to the brain the degree of adiposity and the metabolic status of the organism. The development of leptin and insulin resistance in hypothalamic neurons appears to have a key role in the exacerbation of diet-induced obesity. In rodents, this has been attributed partly to the increased expression of the tyrosine phosphatases Protein Tyrosine Phosphatase 1B (PTP1B) and T cell protein tyrosine phosphatase (TCPTP), which attenuate leptin and insulin signaling. Deficiencies in PTP1B and TCPTP in the brain, or specific neurons, promote insulin and leptin signaling and prevent diet-induced obesity, type 2 diabetes mellitus (T2DM), and fatty liver disease. Although targeting phosphatases and hypothalamic circuits remains challenging, recent advances indicate that such hurdles might be overcome. Here, we focus on the roles of PTP1B and TCPTP in insulin and leptin signaling and explore their potential as therapeutic targets., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The primary task of white adipose tissue (WAT) is the storage of lipids. However, "beige" adipocytes also exist in WAT. Beige adipocytes burn fat and dissipate the energy as heat, but their abundance is diminished in obesity. Stimulating beige adipocyte development, or WAT browning, increases energy expenditure and holds potential for combating metabolic disease and obesity. Here, we report that insulin and leptin act together on hypothalamic neurons to promote WAT browning and weight loss. Deletion of the phosphatases PTP1B and TCPTP enhanced insulin and leptin signaling in proopiomelanocortin neurons and prevented diet-induced obesity by increasing WAT browning and energy expenditure. The coinfusion of insulin plus leptin into the CNS or the activation of proopiomelanocortin neurons also increased WAT browning and decreased adiposity. Our findings identify a homeostatic mechanism for coordinating the status of energy stores, as relayed by insulin and leptin, with the central control of WAT browning., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Leptin is a critical regulator of metabolism, which acts on brain receptors (Lepr) to reduce energy intake and increase energy expenditure. Some of the cellular pathways mediating leptin's anorectic actions are identified, but those mediating the thermogenic effects have proven more difficult to decipher. We define a population of neurons in the dorsomedial hypothalamic nucleus (DMH) containing the RFamide PrRP, which is activated by leptin. Disruption of Lepr selectively in these cells blocks thermogenic responses to leptin and causes obesity. A separate population of leptin-insensitive PrRP neurons in the brainstem is required, instead, for the satiating actions of the gut-derived hormone cholecystokinin (CCK). Global deletion of PrRP (in a loxSTOPlox-PrRP mouse) results in obesity and attenuated responses to leptin and CCK. Cre-recombinase-mediated reactivation of PrRP in brainstem rescues the anorectic actions of CCK, but reactivation in the hypothalamus is required to re-establish the thermogenic effect of leptin., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Reactive oxygen species (ROS) such as H2O2 can promote signaling through the inactivation of protein tyrosine phosphatases (PTPs). However, in obesity, the generation of ROS exceeds the antioxidant reserve and can contribute to the promotion of insulin resistance. Glutathione peroxidase 1 (Gpx1) is an antioxidant enzyme that eliminates H2O2. Here, we have used Gpx1(-/-) mice to assess the impact of oxidative stress on glucose homeostasis in the context of obesity., Results: Gpx1(-/-) mice fed an obesogenic high-fat diet for 12 weeks exhibited systemic oxidative stress and hyperglycemia, but had unaltered whole-body insulin sensitivity, improved hepatic insulin signaling, and decreased whole-body glucose production. High-fat-fed Gpx1(-/-) mice also exhibited decreased hepatic steatosis and liver damage accompanied by decreased plasma insulin and decreased glucose-induced insulin secretion. The decreased insulin secretion was associated with reduced islet β cell pancreatic and duodenal homeobox-1 (Pdx1) and insulin content, elevated pancreatic PTP oxidation (including PTPN2 oxidation), and elevated signal transducer and activator of transcription 1 (STAT1) Y701 phosphorylation., Innovation and Conclusion: Taken together, these results are consistent with H2O2 inactivating pancreatic PTPs (such as the STAT1 phosphatase PTPN2) for the promotion of STAT-1 signaling to suppress Pdx1 expression and differentiation and, consequently, reduce β cell insulin secretion. We propose that the decreased insulin secretion, in turn, results in decreased hepatic lipogenesis and steatosis, attenuates liver damage, and improves hepatic insulin signaling to suppress hepatic glucose production. Limiting insulin secretion may help combat the development of hepatic steatosis and liver damage in diet-induced obesity.

Hemopressin is the first peptide ligand to be described for the CB₁ cannabinoid receptor. Hemopressin acts as an inverse agonist in vivo and can cross the blood-brain barrier to both inhibit appetite and induce antinociception. Despite being highly effective, synthetic CB₁ inverse agonists are limited therapeutically due to unwanted, over dampening of central reward pathways. However, hemopressin appears to have its effect on appetite by affecting satiety rather than reward, suggesting an alternative mode of action which might avoid adverse side effects. Here, to resolve the neuronal circuitry mediating hemopressin's actions, we have combined blood-oxygen-level-dependent, pharmacological-challenge magnetic resonance imaging with c-Fos functional activity mapping to compare brain regions responsive to systemic administration of hemopressin and the synthetic CB₁ inverse agonist, AM251. Using these complementary methods, we demonstrate that hemopressin activates distinct neuronal substrates within the brain, focused mainly on the feeding-related circuits of the mediobasal hypothalamus and in nociceptive regions of the periaqueductal grey (PAG) and dorsal raphe (DR). In contrast to AM251, there is a distinct lack of activation of the brain reward centres, such as the ventral tegmental area, nucleus accumbens and orbitofrontal cortex, which normally form a functional activity signature for the central action of synthetic CB₁ receptor inverse agonists. Thus, hemopressin modulates the function of key feeding-related brain nuclei of the mediobasal hypothalamus, and descending pain pathways of the PAG and DR, and not higher limbic structures. Thus, hemopressin may offer behaviourally selective effects on nociception and appetite, without engaging reward pathways., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Prolactin-releasing peptide (PrRP) was first isolated from bovine hypothalamus, and was found to act as an endogenous ligand at the G-protein-coupled receptor 10 (GPR10 or hGR3). Although originally named as it can affect the secretion of prolactin from anterior pituitary cells, the potential functions for this peptide have been greatly expanded over the past decade. Anatomical, pharmacological, and physiological studies indicate that PrRP, signaling via the GPR10 receptor, may have a wide range of roles in neuroendocrinology; such as in energy homeostasis, stress responses, cardiovascular regulation, and circadian function. This review will provide the current knowledge of the PrRP and GPR10 signaling system, its putative functions, implications for therapy, and future perspectives.

The glucose analogue, 2-deoxy-D-glucose (2-DG) is an inhibitor of glycolysis and, when administered systemically or centrally, induces glucoprivation leading to counter-regulatory responses, including increased feeding behaviour. Investigations into how the brain responds to glucoprivation could have important therapeutic potential, as disruptions or defects in the defence of the brain's 'glucostatic' circuitry may be partly responsible for pathological conditions resulting from diabetes and obesity. To define the 'glucostat' brain circuitry further we have combined blood-oxygen-level-dependent pharmacological-challenge magnetic resonance imaging (phMRI) with whole-brain c-Fos functional activity mapping to characterise brain regions responsive to an orexigenic dose of 2-DG [200 mg/kg; subcutaneous (s.c.)]. For phMRI, rats were imaged using a T(2)*-weighted gradient echo in a 7T magnet for 60 min under alpha-chloralose anaesthesia, whereas animals for immunohistochemistry were unanaesthetised and freely behaving. These complementary methods demonstrated functional brain activity in a number of previously characterised glucose-sensing brain regions such as those in the hypothalamus and brainstem following administration of 2-DG compared with vehicle. As the study mapped whole-brain functional responses, it also identified the orbitofrontal cortex and striatum (nucleus accumbens and ventral pallidum) as novel 2-DG-responsive brain regions. These regions make up a corticostriatal connection with the hypothalamus, by which aspects of motivation, salience and reward can impinge on the hypothalamic control of feeding behaviour. This study, therefore, provides further evidence for a common integrated circuit involved in the induction of feeding behaviour, and illustrates the valuable potential of phMRI in investigating central pharmacological actions.

Hemopressin is a short, nine amino acid peptide (H-Pro-Val-Asn-Phe-Lys-Leu-Leu-Ser-His-OH) isolated from rat brain that behaves as an inverse agonist at the cannabinoid receptor CB(1), and is shown here to inhibit agonist-induced receptor internalization in a heterologous cell model. Since this peptide occurs naturally in the rodent brain, we determined its effect on appetite, an established central target of cannabinoid signaling. Hemopressin dose-dependently decreases night-time food intake in normal male rats and mice, as well as in obese ob/ob male mice, when administered centrally or systemically, without causing any obvious adverse side effects. The normal, behavioral satiety sequence is maintained in male mice fasted overnight, though refeeding is attenuated. The anorectic effect is absent in CB(1) receptor null mutant male mice, and hemopressin can block CB(1) agonist-induced hyperphagia in male rats, providing strong evidence for antagonism of the CB(1) receptor in vivo. We speculate that hemopressin may act as an endogenous functional antagonist at CB(1) receptors and modulate the activity of appetite pathways in the brain.

Endocannabinoids have a variety of effects by acting through cannabinoid 1 (CB1) receptors located throughout the brain. However, since CB1 receptors are located presynaptically, and because the strength of downstream coupling varies with brain region, expression studies alone do not provide a firm basis for interpreting sites of action. Likewise, to date most functional studies have used high doses of drugs, which can bias results toward non-relevant adverse effects, and which mask more behaviourally-relevant actions. Here we use a low, orexigenic dose of the full CB1 agonist, CP55940, to map responsive brain regions using the complementary techniques of pharmacological-challenge functional magnetic resonance imaging (phMRI) and immediate-early gene activity. Areas of interest demonstrate a drug interaction when the CB1 receptor inverse agonist, rimonabant, is co-administered. This analysis highlights the corticostriatal-hypothalamic pathway, which is central to the motivational drive to eat.