Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis
Eric D. BerglundChen LiuJong-Woo SohnTiemin LiuMi Hwa KimCharlotte E. LeeCláudia R. ViannaKevin W. WilliamsYong XuJoel K. Elmquist
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Abstract:
Energy and glucose homeostasis are regulated by central serotonin 2C receptors. These receptors are attractive pharmacological targets for the treatment of obesity; however, the identity of the serotonin 2C receptor-expressing neurons that mediate the effects of serotonin and serotonin 2C receptor agonists on energy and glucose homeostasis are unknown. Here, we show that mice lacking serotonin 2C receptors (Htr2c) specifically in pro-opiomelanocortin (POMC) neurons had normal body weight but developed glucoregulatory defects including hyperinsulinemia, hyperglucagonemia, hyperglycemia, and insulin resistance. Moreover, these mice did not show anorectic responses to serotonergic agents that suppress appetite and developed hyperphagia and obesity when they were fed a high-fat/high-sugar diet. A requirement of serotonin 2C receptors in POMC neurons for the maintenance of normal energy and glucose homeostasis was further demonstrated when Htr2c loss was induced in POMC neurons in adult mice using a tamoxifen-inducible POMC-cre system. These data demonstrate that serotonin 2C receptor-expressing POMC neurons are required to control energy and glucose homeostasis and implicate POMC neurons as the target for the effect of serotonin 2C receptor agonists on weight-loss induction and improved glycemic control.Keywords:
Energy homeostasis
Hyperinsulinemia
Homeostasis
Hypothalamic lactate metabolism regulates hepatic glucose and lipid homeostasis, however it remains unclear whether hypothalamic lactate also controls energy homeostasis. Furthermore, the precise downstream molecular and signaling pathway(s) involved in hypothalamic lactate-sensing is yet to be fully elucidated. To specifically address these two questions, we tested the hypothesis that hypothalamic lactate metabolism regulates energy homeostasis (Study 1) and assessed whether the activation of N-methyl-D-aspartate (NMDA) receptors in the nucleus of the solitary tract (NTS) of the brainstem is required for hypothalamic lactate, and sufficient per se, to regulate glucose homeostasis (Study 2). In an in vivo rat model, we reported in Study 1 that central lactate lowers food intake and body weight through its metabolism into pyruvate. In Study 2, we identified that hypothalamic lactate metabolism requires the activation of NMDA receptors in the NTS to lower hepatic glucose production. Moreover, we showed that the activation of NTS NMDA receptors per se lowers hepatic glucose production. In summary, these findings advance the understanding of central nutrient-sensing in the regulation of energy and glucose homeostasis, which is critical in bridging the therapeutic gap of obesity and type 2 diabetes.%%%%MAST
Energy homeostasis
Homeostasis
Carbohydrate Metabolism
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Aim: Evidences from several studies suggest that probiotics affect glucose homeostasis. This paper reviews the results of animal and human studies on the role of probiotics in modulating glucose homeostasis. Method: A systematic literature search using multiple databases was conducted without time limitation. Primary outcomes evaluated were parameters related to glucose homeostasis. Secondary outcomes were inflammatory markers, lipid profile, body weight, and energy intake. Results: A total of 17 animal studies and four human studies were identified. Among these, 16 animal studies and three human studies had documented significant improvements in at least one glucose homeostasis related parameter. Inflammatory markers and lipid profile were significantly improved in the animal model, while data from human studies were controversial. Changes in body weight and energy intake that could be due to probiotics supplementation were also inconclusive. Conclusion: Well-designed placebo-controlled clinical trials with validated outcome variables are needed to determine the effect of probiotics on glucose homeostasis.
Animal studies
Energy homeostasis
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Abstract Aging is associated with glucose metabolism disturbances, such as insulin resistance and hyperinsulinemia, which contribute to the increased prevalence of type 2 diabetes (T2D) and its complications in the elderly population. In this sense, some bile acids have emerged as new therapeutic targets to treat TD2, as well as associated metabolic disorders. The taurine conjugated bile acid, tauroursodeoxycholic acid (TUDCA) improves glucose homeostasis in T2D, obesity, and Alzheimer's disease mice model. However, its effects in aged mice have not been explored yet. Here, we evaluated the actions of TUDCA upon glucose-insulin homeostasis in aged C57BL/6 male mice (18-month-old) treated with 300 mg/kg of TUDCA or its vehicle. TUDCA attenuated hyperinsulinemia and improved glucose homeostasis in aged mice, by enhancing liver insulin-degrading enzyme (IDE) expression and insulin clearance. Furthermore, the improvement in glucose-insulin homeostasis in these mice was accompanied by a reduction in adiposity, associated with adipocyte hypertrophy, and lipids accumulation in the liver. TUDCA-treated aged mice also displayed increased energy expenditure and metabolic flexibility, as well as a better cognitive ability. Taken together, our data highlight TUDCA as an interesting target for the attenuation of age-related hyperinsulinemia and its deleterious effects on metabolism.
Hyperinsulinemia
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Homeostasis
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Energy homeostasis
Homeostasis
Blood sugar regulation
Metabolic Regulation
Nutrient Sensing
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Dexfenfluramine
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The arcuate nucleus of the hypothalamus is a key regulator of energy balance and glucose homeostasis. In particular, arcuate proopiomelanocortin (POMC) neurons inhibit food intake, stimulate energy expenditure and increase glucose tolerance. The interruption of insulin or glucose signaling in POMC neurons leads to glucose intolerance without changing energy homeostasis. Although it was previously shown that POMC neurons are necessary for normal glucose homeostasis, the participation of POMC neuropeptide, by mechanisms independent of energy balance, remains to be demonstrated. To study the role of POMC in the regulation of glucose homeostasis, we performed glucose and insulin tolerance tests in non-obese mice lacking hypothalamic POMC expression. We found that POMC deficiency leads to glucose intolerance and insulin resistance in female mice before the onset of obesity or hyperphagia. Conversely, POMC deficiency does not impair glucose homeostasis in non-obese male mice. Interestingly, females completely normalize both glucose and insulin tolerance after genetic POMC restoration. Next, to further study sex dimorphism of POMC neurons regarding glucose homeostasis, we measured glucose-elicited changes in C-FOS by performing immunofluorescence in brain slices of POMC-EGFP mice. Remarkably, we found that glucose-induced C-FOS expression in POMC neurons is more than 3-fold higher in female than in male mice. Altogether, our results reveal a key role of arcuate POMC in the regulation of glucose homeostasis in females. Since POMC reactivation completely reverses the diabetogenic phenotype, arcuate POMC could be a potential target for diabetes therapy.
Proopiomelanocortin
Energy homeostasis
Homeostasis
Blood sugar regulation
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Serotonergic agonists such as m-chlorophenylpiperazine (m-CPP) and fenfluramine may induce migraine attacks. This has led to opposing theories concerning the role of 5-hydroxytryptamine (5HT) in triggering migraine attacks; is there hyperfunction or hypofunction of the central serotonergic system. Our review of the literature strongly suggests that m-CPP and fenfluramine provoke migraine attacks by stimulating, directly or indirectly, the 5HT 2C /5HT 2B receptors, although there is no total agreement with this interpretation. Central 5HT hypersensitivity in migraine patients, probably due to 5HT neuronal depletion, is proposed on the basis of review of electrophysiological tests and neuroendocrine challenge paradigms.
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Pharmacological studies have suggested hypothalamic phosphodiesterase-3B to mediate leptin and insulin action in regulation of energy homeostasis. Whereas Pde3b-null mice show altered energy homeostasis, it is unknown whether this is due to ablation of Pde3b in the hypothalamus. Thus, to address the functional significance of hypothalamic phosphodiesterase-3B, we used Pde3bflox/flox and Nkx2.1-Cre mice to generate Pde3b Nkx2.1KD mice that showed 50% reduction of phosphodiesterase-3B in the hypothalamus. To determine the effect of partial ablation of phosphodiesterase-3B in the hypothalamus on energy and glucose homeostasis, males and females were subjected to either a low- or high-fat diet for 19–21 weeks. Only female but not male Pde3b Nkx2.1KD mice on the low-fat diet showed increased body weight from 13 weeks onward with increased food intake, decreased fat pad weights and hypoleptinemia. Glucose tolerance was improved in high-fat diet-fed male Pde3b Nkx2.1KD mice in association with decreased phosphoenolpyruvate carboxykinase-1 and glucose-6-phosphatase mRNA levels in the liver. Also, insulin sensitivity was increased in male Pde3b Nkx2.1KD mice on the low-fat diet. Changes in body weight or in glucose homeostasis were not associated with any alteration in hypothalamic proopiomelanocortin, neuropepide Y and agouti-related peptide mRNA levels. These results suggest that partial loss of phosphodiesterase-3B in the hypothalamus produces a sex-specific response in body weight and glucose homeostasis, and support a role, at least in part, for hypothalamic phosphodiesterase-3B in regulation of energy and glucose homeostasis in mice.
Energy homeostasis
Homeostasis
Proopiomelanocortin
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