Central Neural Regulation of Brown Adipose Tissue Thermogenesis and Energy Expenditure

Morrison, Shaun F.; Madden, Christopher J.; Tupone, Domenico

doi:10.1016/j.cmet.2014.02.007

Cited by 372 publications

(445 citation statements)

References 138 publications

(236 reference statements)

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“…Chronic co-treatment with betahistine also reversed the attenuated BAT UCP 1 and PGC-1α expressions, which illustrated that the two biomarkers of thermogenesis were involved in the decreased energy expenditure and increased weight gain induced by chronic olanzapine treatment [65]. Furthermore, the negative correlation between hypothalamic pAMPKα, and BAT UCP 1 and PGC-1α levels, is in line with the previous report about hypothalamic AMPK modulating BAT thermogenesis, and UCP 1 and PGC-1α expression [184][185][186][187].…”

Section: The Mechanisms Underlying Betahistine In Reducing Antipsychosupporting

confidence: 79%

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Lian

Huang

Pai

et al. 2016

Pharmacological Research

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Second generation antipsychotic drugs (SGAs) cause substantial body weight gain/obesity and other metabolic side-effects such as dyslipidaemia. Their antagonistic affinity to the histaminergic H1 receptor (H1R) has been identified as one of the main contributors to weight gain/obesity side-effects. The effects and mechanisms of betahistine (a histaminergic H1R agonist and H3 receptor antagonist) have been investigated for ameliorating SGA-induced weight gain/obesity in both animal models and clinical trials. It has been demonstrated that co-treatment with betahistine is effective in reducing weight gain, associated with olanzapine in drug-naïve patients with schizophrenia, as well as in the animal models of both drug-naïve rats and rats with chronic, repeated exposure to olanzapine. Betahistine co-treatment can reduce food intake and increase the effect of thermogenesis in brown adipose tissue by modulating hypothalamic H1R-NPY-AMPKα (NPY: neuropeptide Y; AMPKα: AMP-activated protein kinase α) pathways, and ameliorate olanzapineinduced dyslipidaemia through modulation of AMPKα-SREBP-1-PPARα-dependent pathways (SREBP-1: Sterol regulatory element binding protein 1; PPARα: Peroxisome proliferator-activated receptor-α) in the liver. Although reduced locomotor activity was observed from antipsychotic treatment in rats, betahistine did not affect locomotor activity. Importantly, betahistine co-treatment did not influence the effects of antipsychotics on serotonergic receptors in the key brain regions for antipsychotic therapeutic efficacy. However, betahistine co-treatment reverses the upregulated dopamine D2 binding caused by chronic olanzapine administration, which may be beneficial in reducing D2 supersensitivity often observed in chronic antipsychotic treatment. Therefore, these results provide solid evidence supporting further clinical trials in treating antipsychotics-induced weight gain using betahistine in patients with schizophrenia and other mental disorders.

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Section: The Mechanisms Underlying Betahistine In Reducing Antipsychosupporting

confidence: 79%

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Lian

Huang

Pai

et al. 2016

Pharmacological Research

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“…The DMH is a key hypothalamic region governing SNS stimulation of BAT thermogenesis (13,14). Consistent with histology showing inactive BAT in mDMHGsKO mice ( Figure 1H), expression of several BAT genes involved in thermogenesis, including those for PPARγ coactivator 1-α (Pgc1a), cytochrome c ( Figure 4A), and uncoupling protein 1 (Ucp1) ( Figure 4D , RT) were significantly reduced in mDMHGsKO mice.…”

Section: G S α Is Imprinted In Dmhsupporting

confidence: 54%

“…The DMH contains neurons that are polysynaptically connected to BAT via the rostral raphe pallidus and that stimulate SNS activity to BAT, resulting in induction of Ucp1, increased lipid oxi- dation, and thermogenesis (14,(31)(32)(33)(34). We observed that mDMHGsKO mice had an inactive BAT appearance and reduced expression of thermogenic genes in BAT (e.g., Pgc1a, cytochrome c, and Ucp1), and similar BAT histology was observed in DMH-MC4RKO mice.…”

Section: Discussionmentioning

confidence: 56%

Gsα deficiency in the dorsomedial hypothalamus underlies obesity associated with Gsα mutations

Chen

Shrestha

Podyma

et al. 2016

Journal of Clinical Investigation

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“…The current study is, to the best of our knowledge, the first to show that central UGN infusion reduces body weight and adiposity in DIO mice independent of food intake. Indeed, many peripheral signals have been attributed to the regulation of energy expenditure via neuronal pathways, and increasing evidence indicates that BAT activity (23,24) and activation of beige/brown-in-white adipocytes in WAT, a process known as browning (25-27), are controlled by the CNS. Our findings suggest that the mechanisms by which central UGN infusion reduces body weight involve increased energy expenditure through promotion of BAT thermogenesis and the browning of WAT.…”

Section: Discussionmentioning

confidence: 99%

Uroguanylin Action in the Brain Reduces Weight Gain in Obese Mice via Different Efferent Autonomic Pathways

et al. 2015

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The gut-brain axis is of great importance in the control of energy homeostasis. The identification of uroguanylin (UGN), a peptide released in the intestines that is regulated by nutritional status and anorectic actions, as the endogenous ligand for the guanylyl cyclase 2C receptor has revealed a new system in the regulation of energy balance. We show that chronic central infusion of UGN reduces weight gain and adiposity in diet-induced obese mice. These effects were independent of food intake and involved specific efferent autonomic pathways. On one hand, brain UGN induces brown adipose tissue thermogenesis, as well as browning and lipid mobilization in white adipose tissue through stimulation of the sympathetic nervous system. On the other hand, brain UGN augments fecal output through the vagus nerve. These findings are of relevance as they suggest that the beneficial metabolic actions of UGN through the sympathetic nervous system do not involve nondesirable gastrointestinal adverse effects, such as diarrhea. The present work provides mechanistic insights into how UGN influences energy homeostasis and suggests that UGN action in the brain represents a feasible pharmacological target in the treatment of obesity.After the ingestion of a meal, the presence of nutrients in the gastrointestinal (GI) tract initiates complex neural and hormonal responses that send signals to the brain about the ongoing changes in nutritional status. Among the different strategies used to communicate to the brain, the gut secretes peptides that reach the central nervous system (CNS) via afferent nerve fibers or the circulation (1,2). New gut hormones are continuously discovered, and, with the exception of ghrelin, which is the only peptidic hormone favoring weight gain and adiposity, all of them are associated with a negative energy balance and are thus potential targets for the treatment of obesity (3,4).One of the most recently discovered gut hormones is uroguanylin (UGN), a 16-amino acid peptide secreted mainly from duodenal epithelial cells. UGN is synthesized as a prohormone (pro-UGN), which, after cleavage by a still unknown enzyme, is converted to the active UGN (3,5). Both pro-UGN and UGN activate the guanilate cyclase 2C receptor (GUCY2C), which is also targeted by diarrheagenic bacterial heat-stable enterotoxins (STs) (6). The activation of GUCY2C leads to elevated intracellular levels of cyclic guanosine monophosphate (7), which in invertebrate species has been demonstrated to lead to alterations in food behavior and energy-balance regulation (8,9). Circulating UGN levels were decreased in fasted and leptin-deficient mice but recovered after refeeding or exogenous leptin

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Central Neural Regulation of Brown Adipose Tissue Thermogenesis and Energy Expenditure

Cited by 372 publications

References 138 publications

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Gsα deficiency in the dorsomedial hypothalamus underlies obesity associated with Gsα mutations

Uroguanylin Action in the Brain Reduces Weight Gain in Obese Mice via Different Efferent Autonomic Pathways

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