Regulation of thermogenesis by the central melanocortin system

Fan, Wei; Voss-Andreae, Adriana; Cao, Weihua; Morrison, Shaun F.

doi:10.1016/j.peptides.2004.11.033

Cited by 68 publications

(48 citation statements)

References 159 publications

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“…Adaptive thermogenesis is the process by which energy is dissipated in the form of heat in response to environmental changes such as exposure to cold and alterations in diet (Spiegelman & Flier 2001). Under homeostatic conditions, adaptive thermogenesis is a key mechanism by which body maintains core temperature and regulates EE, and its dysregulation promotes obesity (Fan et al 2005).…”

Section: Discussionmentioning

confidence: 99%

PARP1 deficiency exacerbates diet-induced obesity in mice

Devalaraja-Narashimha¹,

Padanilam

2010

Journal of Endocrinology

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Poly (ADP-ribose) polymerase-1 (PARP1) regulates gene expression as a transcriptional cofactor and protein functions via poly (ADP-ribosyl)ation. This study was aimed to determine the effect of Parp1 gene deficiency on diet-induced obesity and energy metabolism. Parp1-knockout (Parp-KO) and wild-type (WT) mice on the same genetic background were fed either normal chow or high-fat (HF) diet. Food intake and weight gain were monitored weekly. Plasma levels of glucose, leptin, and insulin were monitored monthly. At 19 weeks, locomotor activity, body composition, respiratory quotient and heat production, glucose and insulin tolerance, and fat reabsorption were analyzed. Parp-KO mice are highly susceptible to diet-induced obesity, accumulation of fat tissue, and they develop hyperleptinemia and insulin resistance and glucose intolerance compared with their WT counterparts. The increased weight gain is due to decreased metabolic rate, heat production, and total energy expenditure (EE). Paradoxically, food intake is less, and the motor activity and oxidation of fat are higher in Parp-KO mice. Absorption of fatty acids is not altered between the groups after HF diet. These results suggest that malfunction of PARP1 signaling exacerbates diet-induced obesity, hyperleptinemia, and insulin resistance, and that it decreases EE in 129 mice.

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Section: Discussionmentioning

confidence: 99%

PARP1 deficiency exacerbates diet-induced obesity in mice

Devalaraja-Narashimha¹,

Padanilam

2010

Journal of Endocrinology

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“…NE released from sympathetic nerve terminals activates b 3 -adrenoceptors on brown adipocytes in BAT and leads to lipolysis, increased activity of uncoupling protein-1 (UCP-1), and thermogenesis (Avram et al, 2005;Fan et al, 2005). By blocking NE reuptake in sympathetic nerve terminals, an NE reuptake inhibitor could increase b 3 -adrenoceptor activation, thereby increasing oxidative phosphorylation and the production of heat (Iversen, 1971).…”

Section: Discussionmentioning

confidence: 99%

“…BUP has been shown to increase DA and NE in hypothalamic nuclei that regulate body temperature such as the preoptic area and anterior hypothalamus . Catecholamine reuptake inhibitors may also affect activity of cells in the hypothalamic melanocortin system, which regulates caloric intake and metabolic rate in response to energy availability (Fan et al, 2005;Ramos et al, 2005). For example, activation of the dopamine D2 receptor increases expression of anorexic pro-opiomelanocortin mRNA and decreases expression of orexigenic neuropeptide Y mRNA within the arcuate nucleus of the hypothalamus (Pelletier and Simard, 1991;Tong and Pelletier, 1992).…”

Section: Discussionmentioning

confidence: 99%

Catecholamine Reuptake Inhibition Causes Weight Loss by Increasing Locomotor Activity and Thermogenesis

Billes

Cowley

2007

Neuropsychopharmacol

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Bupropion (BUP) is a dopamine (DA) and norepinephrine (NE) reuptake inhibitor that causes mild weight loss in obese adults. Subchronic (7 day) coadministration of selective DA and NE reuptake inhibitors also causes weight loss in mice. Because weight loss was not associated with decreased caloric intake, subchronic BUP might cause weight loss through increased energy expenditure. Acute studies demonstrate that BUP or DA + NE reuptake inhibitors cause transient hypophagia and increased locomotion; though the effects on temperature are inconsistent. Because subchronic DA + NE reuptake inhibition does not affect appetite, there is clearly a difference between the acute and subchronic effects of DA + NE reuptake inhibitors; however the effects of chronic (or subchronic) BUP on energy balance have never been directly studied in an animal model. Therefore, the acute and subchronic effects of BUP or selective DA and NE reuptake inhibitors on food intake, body weight, locomotor activity, and interscapular temperature were determined in mice. Generally, selective inhibition of DA reuptake (by GBR12783) increased activity while selective inhibition of NE reuptake (by nisoxetine, NIS) decreased activity and temperature. BUP increased activity and temperature but subchronic BUP did not significantly reduce body weight due to a compensatory increase in food intake. Subchronic DA + NE reuptake inhibitor coadministration mimicked the effect of BUP on activity and temperature, but caused weight loss because daily food intake was not increased. The results of this study suggest that the mild weight loss effect of BUP in humans may be due to increased locomotion or heat production. More importantly, inhibition of DA + NE reuptake (with GBR + NIS) increased energy expenditure without a compensatory increase in food intake, supporting a role for novel combination catecholamine reuptake inhibitors in pharmacotherapy for obesity.

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“…MC4R has high affinity for a-melanocyte stimulating hormone (a-MSH) (1), while the receptor is inhibited by endogenous agouti-related protein (AgRP) (2). Stimulation of MC4R decreases food intake and increases energy expenditure (3,4). Less is known about the regulation of hypothalamic MC4R expression.…”

Section: Introductionmentioning

confidence: 99%

Melanocortin 4 receptor distribution in the human hypothalamus

Siljee

Unmehopa

Kalsbeek

et al. 2013

European Journal of Endocrinology

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Objective: The melanocortin 4 receptor (MC4R) is an essential regulator of energy homeostasis and metabolism, and MC4R mutations represent the most prevalent monogenetic cause of obesity in humans known to date. Hypothalamic MC4Rs in rodents are well characterized in neuroanatomical and functional terms, but their expression pattern in the human hypothalamus is unknown. Design and methods: To determine the topographic distribution and identity of cells expressing MC4R mRNA in the human hypothalamus, locked nucleic acid in situ hybridization was performed on nine human postmortem hypothalami. In addition, co-expression of MC4R with glial fibrillary acidic protein (GFAP), vasopressin/oxytocin (AVP/OXT), corticotropin-releasing hormone (CRH), neuropeptide Y (NPY), agouti-related protein (AgRP), and a-melanocyte stimulating hormone (a-MSH) was examined. Results: Most intense MC4R mRNA expression was present in the paraventricular nucleus (PVN), the supraoptic nucleus (SON), and the nucleus basalis of Meynert. Most MC4R-positive cells in the SON also expressed AVP/OXT. Co-expression with AVP/OXT in the PVN was less abundant. We did not observe co-expression of MC4R mRNA and GFAP, CRH, NPY, AgRP, or a-MSH. However, fiber-like staining of NPY, AgRP, and a-MSH was found adjacent to MC4R-positive cells in the PVN. Conclusion: Expression of MC4R mRNA in the human hypothalamus is widespread and in close approximation to endogenous MC4R binding partners AgRP and a-MSH.

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Regulation of thermogenesis by the central melanocortin system

Cited by 68 publications

References 159 publications

PARP1 deficiency exacerbates diet-induced obesity in mice

PARP1 deficiency exacerbates diet-induced obesity in mice

Catecholamine Reuptake Inhibition Causes Weight Loss by Increasing Locomotor Activity and Thermogenesis

Melanocortin 4 receptor distribution in the human hypothalamus

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