The central melanocortin system directly controls peripheral lipid metabolism

Nogueiras, Rubén; Wiedmer, Petra; Pérez-Tilve, Diego; Veyrat-Durebex, Christelle; Keogh, Julia M.; Sutton, Gregory M.; Pfluger, Paul T.; Castañeda, Tamara R.; Neschen, Susanne; Hofmann, Susanna M.; Howles, Philip N.; Morgan, Donald A.; Benoit, Stephen C.; Szántó, Ildikó; Schrott, Brigitte; Schürmann, Annette; Joost, Hans‐Georg; Hammond, Craig; Hui, David Y.; Woods, Stephen C.; Rahmouni, Kamal; Butler, Andrew A.; Farooqi, I. Sadaf; O’Rahilly, Stephen; Rohner‐Jeanrenaud, Françoise; Tschöp, Matthias H.

doi:10.1172/jci31743

Cited by 357 publications

(361 citation statements)

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“…The hypothalamus not only regulates food intake and energy expenditure but also the utilisation and partitioning of nutrients (13) , the regulation of glucose homoeostasis (14) and peripheral lipid metabolism (15)(16)(17) . Two important anorexigenic hormones that signal adiposity and nutritional status to the hypothalamus and inhibit food intake are leptin, produced by white adipose tissue (WAT), and insulin, produced by the pancreatic b-cells.…”

Section: Proceedings Of the Nutrition Societymentioning

confidence: 99%

Hypothalamic dysfunction in obesity

Williams

2012

Proc. Nutr. Soc.

116

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A growing number of studies have shown that a diet high in long chain SFA and/or obesity cause profound changes to the energy balance centres of the hypothalamus which results in the loss of central leptin and insulin sensitivity. Insensitivity to these important anorexigenic messengers of nutritional status perpetuates the development of both obesity and peripheral insulin insensitivity. A high-fat diet induces changes in the hypothalamus that include an increase in markers of oxidative stress, inflammation, endoplasmic reticulum (ER) stress, autophagy defect and changes in the rate of apoptosis and neuronal regeneration. In addition, a number of mechanisms have recently come to light that are important in the hypothalamic control of energy balance, which could play a role in perpetuating the effect of a high-fat diet on hypothalamic dysfunction. These include: reactive oxygen species as an important second messenger, lipid metabolism, autophagy and neuronal and synaptic plasticity. The importance of nutritional activation of the Toll-like receptor 4 and the inhibitor of NF-kB kinase subunit b/NK-kB and c-Jun amino-terminal kinase 1 inflammatory pathways in linking a high-fat diet to obesity and insulin insensitivity via the hypothalamus is now widely recognised. All of the hypothalamic changes induced by a high-fat diet appear to be causally linked and inhibitors of inflammation, ER stress and autophagy defect can prevent or reverse the development of obesity pointing to potential drug targets in the prevention of obesity and metabolic dysfunction.Hypothalamus: Obesity: High-fat diet: Inflammation: Neuronal and synaptic plasticityThe developed world is currently facing an epidemic of obesity. Diseases associated with obesity, particularly type 2 diabetes, CVD, cancer, stroke and mental health issues, including dementia (1,2) are provoking a crisis in health care, adversely affecting health and life expectancy and increasing health care costs, estimated to be up to £45 billion by 2050 in the UK alone (3) . Direct and indirect costs of type 2 diabetes, for example, one of the major health consequences of obesity, are currently £21 . 8 billion and set to rise to £35 . 6 billion by 2035-36 in the UK (4) .Obesity is the result of a disproportionately high energy intake compared to energy expenditure and is a complex interaction between environmental and genetic factors (5) with monogenic defects being relatively rare (6) . It seems obvious that an energy-dense diet, high in saturated fat and sugar, should cause weight gain and increased adiposity; nonetheless it appears that these diets cause a profound change in energy balance that does not result from a simple increase in energetic intake. Diet composition, particularly the presence of long-chain saturated fats, results in metabolic dysfunction and increased adiposity and body weight, Abbreviations: AgRP, agouti-related peptide; ARC, arcuate nuclei; CART, cocaine and amphetamine-regulated transcript; CNTF, ciliary neurotrophic factor; ER, endoplasmic reticulum; I...

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Section: Proceedings Of the Nutrition Societymentioning

confidence: 99%

Hypothalamic dysfunction in obesity

Williams

2012

Proc. Nutr. Soc.

116

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“…This pathway may, therefore, provide the explanation as to how central administration of leptin (Buettner et al, 2008), ghrelin (Theander-Carrillo et al, 2006), neuropeptide Y (Zarjevski et al, 1994), and melanocortins (Nogueiras et al, 2007) control adipocyte metabolism. Because GLP-1 analogues are now approved and widely used as a therapeutic adjunct for human metabolic disease, we asked whether CNS GLP-1 action directly modulates peripheral lipid metabolism, and we demonstrate for the first time that CNS GLP-1 potently and rapidly decreases lipid deposition in WAT and liver.…”

Section: Introductionmentioning

confidence: 99%

Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity

Nogueiras¹,

Pérez-Tilve²,

et al. 2009

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We investigated a possible role of the central glucagon-like peptide (GLP-1) receptor system as an essential brain circuit regulating adiposity through effects on nutrient partitioning and lipid metabolism independent from feeding behavior. Both lean and diet-induced obesity mice were used for our experiments. GLP-1 (7-36) amide was infused in the brain for 2 or 7 d. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR or Western blot. To test the hypothesis that the sympathetic nervous system may be responsible for informing adipocytes about changes in CNS GLP-1 tone, we have performed direct recording of sympathetic nerve activity combined with experiments in genetically manipulated mice lacking ␤-adrenergic receptors. Intracerebroventricular infusion of GLP-1 in mice directly and potently decreases lipid storage in white adipose tissue. These effects are independent from nutrient intake. Such CNS control of adipocyte metabolism was found to depend partially on a functional sympathetic nervous system. Furthermore, the effects of CNS GLP-1 on adipocyte metabolism were blunted in diet-induced obese mice. The CNS GLP-1 system decreases fat storage via direct modulation of adipocyte metabolism. This CNS GLP-1 control of adipocyte lipid metabolism appears to be mediated at least in part by the sympathetic nervous system and is independent of parallel changes in food intake and body weight. Importantly, the CNS GLP-1 system loses the capacity to modulate adipocyte metabolism in obese states, suggesting an obesity-induced adipocyte resistance to CNS GLP-1.

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“…Lipogenic enzyme mRNA levels, such as that encoding fatty acid synthase, are increased in MC4-R −/− and DIO mice (11) and after treatment of WT mice with the dual MC3-R/MC4-R antagonist, SHU9119 (12) but not in the MC3-R −/− mouse (11). In contrast, deletion of the MC3-R produces an obesity syndrome with a loss in lean mass and increase in adipose mass (13,14).…”

mentioning

confidence: 99%

Melanocortin-3 receptor regulates the normal fasting response

Renquist

Murphy

Larson

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The melanocortin-3 receptor-deficient (MC3-R −/− ) mouse exhibits mild obesity without hyperphagia or hypometabolism. MC3-R deletion is reported to increase adiposity, reduce lean mass and white adipose tissue inflammation, and increase sensitivity to salt-induced hypertension. We show here that the MC3-R −/− mouse exhibits defective fasting-induced white adipose tissue lipolysis, fasting-induced liver triglyceride accumulation, fasting-induced refeeding, and fasting-induced regulation of the adipostatic and hypothalamic-adrenal-pituitary axes. Close examination of the hypothalamic-pituitary-adrenal axis showed that MC3-R −/− mice exhibit elevated nadir corticosterone as well as a blunted fasting-induced activation of the axis. The previously described phenotypes of this animal and the reduced bone density reported here parallel those of Cushing syndrome. Thus, MC3-R is required for communicating nutritional status to both central and peripheral tissues involved in nutrient partitioning, and this defect explains much of the metabolic phenotype in the model. energy homeostasis | nonesterified fatty acid | corticotrophin-releasing hormone | hormone-sensitive lipase R esearch on the central melanocortin system has focused on the role of the melanocortin-4 receptor (MC4-R) in energy homeostasis, particularly as a result of the hyperphagic obesity syndrome found in both mice and humans with mutations in this receptor (1-3). A large body of work has demonstrated that circuitry regulated by the MC4-R is essential for much of leptin action and coordinates energy intake with energy expenditure to maintain long-term energy homeostasis (4). In contrast, the melanocortin-3 receptor (MC3-R), expressed in ∼35 different nuclei in the CNS with a pattern distinct from that of the MC4-R

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The central melanocortin system directly controls peripheral lipid metabolism

Cited by 357 publications

References 67 publications

Hypothalamic dysfunction in obesity

Hypothalamic dysfunction in obesity

Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity

Melanocortin-3 receptor regulates the normal fasting response

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