Central melanocortin receptors regulate insulin action

Abstract

IntroductionInsulin resistance is regarded as the main link between obesity and type 2 diabetes mellitus (1, 2). While multiple hypotheses have been proposed to explain this association, recent discoveries on the regulation of feeding behavior and energy expenditure (3-6) have refocused attention on the potential role of hypothalamic centers in the regulation of both energy homeostasis and insulin action (Figure 1) (7-13). In fact, leptin has potent effects on glucose tolerance and insulin action, which appear to be independent of its modulation of feeding behavior (7,9,13). Leptin exerts its actions on food intake and weight gain partly by activation of the melanocortin pathway in the hypothalamus and in other areas within the central nervous system (14). The pivotal role of melanocortinergic neurons in the regulation of energy balance is supported by solid genetic (15, 16) and pharmacologic (17) evidence.To examine whether the activity of the melanocortin pathway in the hypothalamus modulates insulin action in vivo we used the natural agonist, α-melanocyte-stimulating hormone (α-MSH), and a high-affinity antagonist (SHU9119) of the neural melanocortin receptors type 3 and 4 (MCR3, MCR4) (17) to generate bidirectional variations in the activity of this pathway. Body composition and metabolic parameters were assessed using tracer dilution techniques and pancreatic-insulin clamp studies in conscious rats. MethodsExperimental procedures. Thirty-nine male Sprague-Dawley rats (Charles River Laboratories, Wilmington, Massachusetts, USA) were studied ( Figure 2). Rats were housed in individual cages and subjected to a standard light-dark (0600 to 1800 hours/1800 to 0600 hours) cycle. Three weeks before the in vivo study, rats (at ∼10 weeks of age) were equipped with chronic catheters placed in the third cerebral ventricle (18). Rats were anesthetized with intraperitoneal ketamine (Ketaset; 87 mg/kg) and xylazine (Rompun; 11 mg/kg) and fixed in a stereotaxic apparatus with ear bars and a nose piece set at +5.0 mm. A 26-gauge stainless steel guide cannula (Plastics One Inc., Roanoke, Virginia, USA) was chronically implanted into the third ventricle using the following coordinates from bregma: anterior-posterior; +0.2 mm, dorsal-ventral; -9.0 mm, medial-lateral; 0.0 directly on the midsagittal suture. A 28-gauge dummy cannula was inserted to prevent clogging of the guide cannula. The implant is secured to the skull with Caulk Grip dental cement, and the skin is closed over the implant using wound clips. One week before the study, rats (at ∼12 weeks of age) were anesthetized with an intraperitoneal injection of pentobarbital (50 mg/kg body weight), and indwelling catheters were inserted in the right internal jugular vein and in the left carotid artery (18-21). The venous catheter was extended to the level of the right atrium, and the arterial catheter was advanced to the level of the aortic arch. All studies were performed in awake, unstressed, chronically catheterized rats. Histological verification of the intracerebrove...

Hypothalamic pro-opiomelanocortin gene delivery ameliorates obesity and glucose intolerance in aged rats

“…Central Pomc gene therapy partially normalised glucose levels during IPGTT, and also reduced serum insulin levels markedly at all time points after glucose loading. These data are indicative of improved glucose metabolism and insulin sensitivity by Pomc gene delivery and in agreement with previous findings that central melanocortin receptor activation suppresses insulin release from the pancreas and enhances glucose metabolism [2,6,22,38,45]. Since glucose metabolism was not significantly improved on day 20 after Pomc gene delivery, when the differences in body weight reduction and visceral adiposity levels were not as large as those on day 36, it suggests that the improvement in glucose metabolism is mainly the consequence of the decreased food consumption and body weight rather than the direct result of central Pomc overexpression.…”

“…Melanocortins are bioactive peptides derived from a common prehormone, pro-opiomelanocortin (POMC); the central melanocortin system plays a critical role in the regulation of energy balance and glucose metabolism [1][2][3][4][5][6]. Reduced expression of hypothalamic Pomc is associated with obesity syndromes caused by: (1) mutations in any of several genes, including leptin receptor [7,8], tubby [9] and Nhlh2 [10]; (2) hypothalamic damage [11]; and (3), perhaps most commonly, by ageing [12].…”

Body weight is regulated by the brain: a link between feeding and emotion

“…Put another way, this model predicts that both the direct Arc-IML and indirect Arc-PVH-IML pathways likely contribute to the autonomic and metabolic effects of melanocortin receptor agonists. [138][139][140][141] Combinations of genetic and anatomic approaches to characterize leptin-melanocortin signaling CNS circuits 1. Deletion of leptin receptors specifically from POMC neurons: As stressed above, a large body of evidence indicates that POMC neurons in the Arc mediate leptin action.…”

“…138 The MC4-R is also involved in sensitizing peripheral tissue to insulin action. [139][140][141] Centrally administered a-MSH markedly enhances insulin action on glucose uptake as well as on hepatic glucose production, whereas MC4-R antagonism exerts opposite effects. 139 Finally, patients with MC4-R mutations are very insulin-resistant.…”

“…[139][140][141] Centrally administered a-MSH markedly enhances insulin action on glucose uptake as well as on hepatic glucose production, whereas MC4-R antagonism exerts opposite effects. 139 Finally, patients with MC4-R mutations are very insulin-resistant. 84 Collectively, these findings suggest that dysregulation of the 5-HTdriven melanocortin system may be involved in obesity and diabetes as adverse effects of antipsychotic agents.…”