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...

Pancreatic neuronal melanocortin-4 receptor modulates serum insulin levels independent of leptin receptor

“…Collectively, the data suggest a neuronal communication pathway that involves interaction between central and peripheral neuronal pancreatic MC system. The study also added further weight to previous findings that showed that dose-dependent inhibition of serum insulin in ob/ob leptin deficient mice treated centrally with a-MSH and/or synthetic MTII peptides [10,11].…”

“…In addition to a key role in regulation of energy homeostasis [8], studies in wild-type, leptin deficient ob/ob mice, and in mice with diet-induced obesity showed that intracerebroventricular (icv) treatment with melanocortin peptide agonists regulates insulin action and reduces serum insulin levels [10][11][12]. For instance, a-MSH enhanced insulin actions on glucose uptake and production [11], whereas synthetic a-MSH analog MTII inhibited basal insulin secretion in a dose-dependent fashion when administered via an icv cannula [10]. These MTII findings were further solidified by observations of increased plasma insulin concentration in young lean Mc4r null mice before they were physically obese.…”

Central nervous system and control of endogenous glucose production

“…These rapid metabolic effects stand in sharp contrast with the insulin-sensitizing effects of prolonged activation of the central melanocortin receptors [19]. Acute ICV infusion of leptin during insulin clamp studies increases the hepatic expression of PEPCK, Glc-6-Pase, and the rate of gluconeogenesis.…”

“…Prolonged administration of recombinant leptin to nondiabetic and diabetic rodent models [15,16] as well as to lipodystrophic humans [17] and mice [18] markedly improves in vivo insulin action. Similarly, bidirectional modulation of the activity of the central melanocortin pathway leads to significant changes in hepatic and peripheral insulin action, independent of changes in food intake [19]. However, prolonged administration of leptin or melanocortin agonists affects the amount and distribution of body adiposity as well as lipid homeostasis, which could secondarily influence insulin sensitivity and metabolic homeostasis [15,19].…”

“…Similarly, bidirectional modulation of the activity of the central melanocortin pathway leads to significant changes in hepatic and peripheral insulin action, independent of changes in food intake [19]. However, prolonged administration of leptin or melanocortin agonists affects the amount and distribution of body adiposity as well as lipid homeostasis, which could secondarily influence insulin sensitivity and metabolic homeostasis [15,19]. Thus, the direct effects of leptin and melanocortins on metabolic fluxes should be assessed in the absence of changes in body composition and lipid storage.…”