Summary The melanocortin system regulates metabolic homeostasis and inflammation. Melanocortin agonists have contradictorily been reported to both increase and decrease metabolic rate and body temperature. We find two distinct physiologic responses occurring at similar doses. Intraperitoneal administration of the nonselective melanocortin agonist MTII causes a melanocortin-4 receptor (Mc4r) mediated hypermetabolism/hyperthermia. This is preceded by a profound, transient hypometabolism/hypothermia that is preserved in mice lacking any one of Mc1r, Mc3r, Mc4r, or Mc5r. Three other melanocortin agonists also caused hypothermia, which is actively achieved via seeking a cool environment, vasodilation, and inhibition of brown adipose tissue thermogenesis. These results suggest that the hypometabolic/hypothermic effect of MTII is not due to a failure of thermoregulation. The hypometabolism/hypothermia was prevented by dopamine antagonists and MTII selectively activated arcuate nucleus dopaminergic neurons; these neurons may contribute to the hypometabolism/hypothermia. We propose that the hypometabolism/hypothermia is a regulated response, potentially beneficial during extreme physiologic stress.

Metabolic syndrome consists of hypertension, insulin resistance, dyslipidemia and fatty liver. Thiazides are the leading treatment for hypertension, but some clinical studies have suggested adverse metabolic effects. We sought for the first time to characterize the metabolic effects of thiazides in an animal model of metabolic syndrome. SHROB rats are obese, hypertensive and express every component of human metabolic syndrome. Adult female SHROB rats (N=6 per group) were fed a purified diet (AIN 93) replete with electrolytes and treated in their drinking water for 5 weeks with either vehicle (250 ppm saccharine and 100 ppm sodium benzoate) or hydrochlorothiazide (achieved dose of 44±2 mg/kg/d). Systolic blood pressure fell progressively from 184±5 to 142±2 mmHg with thiazide treatment while remaining unchanged in controls. Heart rate was not affected. Body weight, food intake, and water intake did not differ between groups, nor did fasting glucose or insulin. Oral glucose tolerance testing (6 g/kg by gavage after an 18h fast) showed increased plasma glucose levels in the thiazide group (at 60 min post load, 394±48 vs 214±51 mg/dL in controls, P<0.05 by t‐test). Insulin levels at the same time were half again higher in SHROB treated with thiazide (90±20 vs 61±14 ng/mL in controls, NS, but two‐way ANOVA shows a difference, P<0.05 by F‐test). Relative liver mass was increased in the thiazide group relative to controls (43±3 vs 35±3 g/kg body weight, P<0.05 by t‐test). Thus, thiazide was an effective antihypertensive therapy in the SHROB model of metabolic syndrome but worsened glucose tolerance and insulin resistance and enlarged the already fatty liver. The secretory response of the pancreas to glucose was apparently not impaired or even increased, suggesting that insulin signaling may be affected by thiazides.Research support for this study was given by Ophthalmology Education Worldwide