We evaluated the role of the melanocortin-4 receptor (MC-4R) in the control of metabolic rate and food intake in mice. Intraperitoneal administration of the non-selective MC-R agonist melanotan II (MT-II; a cyclic heptapeptide) increases metabolic rate in wildtype mice, while MC-4R knockout mice are insensitive to the effects of MT-II on metabolic rate. MC-4R knockout mice are also insensitive to the effects of MT-II on reducing food intake. We conclude that MC-4R can mediate control of both metabolic rate and food intake in mice. We infer that a role for MC-3R in mediating the acute effects of MT-II on basal metabolic rate and food intake in wildtype mice seems limited.

No abstract

Background and purpose: Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide expressed in the lateral hypothalamus that is involved in feeding and body weight regulation. Intracerebroventricular infusion of a peptidic MCH1 receptor antagonist ameliorated obesity in murine models. Recently, small molecule MCH1 receptor antagonists have been developed and characterized for the treatment of obesity. However, little is known of the mechanism of the anti-obesity effects of MCH1 receptor antagonists. Experimental approach: To examine the mechanisms of action of the anti-obesity effect of MCH1 receptor antagonists more precisely, we conducted a pair-feeding study in mice with diet-induced obesity (DIO), chronically treated with an orally active and highly selective MCH1 receptor antagonist and examined changes in mRNA expression levels in liver, brown and white adipose tissues. We also assessed the acute effects of the MCH1 receptor antagonist in energy expenditure under thermoneutral conditions. Key results: Treatment with the MCH1 receptor antagonist at 30 mg·kg -1 for 1 month moderately suppressed feeding and significantly reduced body weight by 24%. In contrast, pair-feeding resulted in a smaller weight reduction of 10%. Treatment with the MCH1 receptor antagonist resulted in a higher body temperature compared with the pair-fed group. TaqMan and calorimetry data suggested that the MCH1 receptor antagonist also stimulated thermogenesis. Conclusions and implications:Our results indicate that an MCH1 receptor antagonist caused anti-obesity effects im mice by acting on both energy intake and energy expenditure.

An isomorphic, dynamic model of the antidiuretic medulla and distal tubule was used to determine how vasa recta (VR) plasma flow and the nature of descending limb (DLH) equilibration influences inner medullary urine concentrating ability in the steady state. Four DLH modes were examined: water recycling with limited solute permeability, ideal water recycling, mixed water-solute recycling, and strict solute recycling. Each DLH mode was evaluated with and without thin ascending limb (tALH) NaCl active transport. Results indicate that VR plasma flow strongly affects medullary solute accumulation, that NaCl reabsorption from passive tALH is insufficient to establish a positive corticomedullary NaCl gradient, that even limited DLH solute entry compromises the medulla's ability to establish an axial osmotic gradient without active transport, and that with tALH active NaCl transport, positive inner medullary NaCl and osmotic gradients could be established with all four DLH modes. We conclude that tALH NaCl active transport or some other form of osmotic work must be invoked to account quantitatively for inner medullary concentrating effects in rodents.

Two models of ypertonic urine formation in the inner medulla were tested. The active model asserts that thin ascending limbs of Henle's loop (ALH) reasorb NaCl hypertonically by active transport; the passive model suggests the reabsorption is by diffusion down a concentration gradient. Using (Na+) in ascending vasa recta (AVR) as a measure of interstitial (Na+), we found no concentration difference between loop tubular fluid and AVR, when the comparison was made at the bend of the loop, or at an ALH sampling site 1 mm from the bend; the results were the same in antidiuresis and saline diuresis. In saline diuresis with flow of tubular fluid to the ALH slowed by simultaneous collection at the bend of the loop,ALH (Na+) fell below AVR levels, a result consistent with active transport, but not with a purely passive mechanism. Although contragradient transport was shown only with flow slowed and the corticomedullary gradient reduced, a model suggests the active component contributes almost half the observed Na+ flux in antidiuresis.