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.

Bombesin receptor subtype-3 (BRS-3) regulates energy homeostasis, with Brs3 knockout (Brs3 Ϫ/y ) mice being hypometabolic, hypothermic, and hyperphagic and developing obesity. We now report that the reduced body temperature is more readily detected if body temperature is analyzed as a function of physical activity level and light/dark phase. Physical activity level correlated best with body temperature 4 min later. The Brs3 Ϫ/y metabolic phenotype is not due to intrinsically impaired brown adipose tissue function or in the communication of sympathetic signals from the brain to brown adipose tissue, since Brs3 Ϫ/y mice have intact thermogenic responses to stress, acute cold exposure, and ␤3-adrenergic activation, and Brs3 Ϫ/y mice prefer a cooler environment. Treatment with the BRS-3 agonist MK-5046 increased brown adipose tissue temperature and body temperature in wild-type but not Brs3 Ϫ/y mice. Intrahypothalamic infusion of MK-5046 increased body temperature. These data indicate that the BRS-3 regulation of body temperature is via a central mechanism, upstream of sympathetic efferents. The reduced body temperature in Brs3 Ϫ/y mice is due to altered regulation of energy homeostasis affecting higher center regulation of body temperature, rather than an intrinsic defect in brown adipose tissue.bombesin receptor subtype-3; obesity; sympathetic nervous system; brown adipose tissue; thermoregulation; CL316243; MK-5046 OBESITY, AN IMBALANCE BETWEEN energy intake and energy expenditure, is associated with several comorbidities, including diabetes mellitus and cardiovascular disease. Current treatments for obesity are inadequate, stimulating research to better understand the physiology of energy homeostasis and to develop safe and effective pharmacologic treatments. The study of bombesin receptor subtype-3 (BRS-3) can advance both of these objectives.BRS-3 is a G protein-coupled receptor for which the natural ligand is unknown, and despite its name, BRS-3 has a low affinity for bombesin and related natural peptides (7,17,21). In addition to other locations, BRS-3 is present in the central nervous system, including the hypothalamus and caudal brainstem (10,16,26,37), regions involved in the regulation of feeding, energy expenditure, and body weight (32). Genetic and pharmacologic studies demonstrate a role for BRS-3 in energy homeostasis. Brs3 knockout (Brs3 Ϫ/y ) mice exhibit hyperphagia, reduced metabolic rate, and obesity (18, 27), and pharmacological blockade of BRS-3 in rats increases food intake and body weight (10). Conversely, BRS-3 agonists reduced food intake, increased metabolic rate and body temperature (Tb), and reduced body weight in mice, rats, and dogs (10,11,22).Currently, the mechanisms underlying Tb regulation by BRS-3 are unclear. Brown adipose tissue (BAT) is the major site of facultative thermogenesis, dissipating chemical energy via uncoupling protein 1 (UCP1), thereby generating heat and maintaining Tb (2). BAT activity is regulated by sympathetic neural input, with upstream regulation from hypot...

Lateef DM, Xiao C, Brychta RJ, Diedrich A, Schnermann J, Reitman ML. Bombesin-like receptor 3 regulates blood pressure and heart rate via a central sympathetic mechanism. Am J Physiol Heart Circ Physiol 310: H891-H898, 2016. First published January 22, 2016; doi:10.1152/ajpheart.00963.2015.-Bombesin-like receptor 3 (BRS-3) is an orphan G protein-coupled receptor that regulates energy expenditure, food intake, and body weight. We examined the effects of BRS-3 deletion and activation on blood pressure and heart rate. In free-living, telemetered Brs3 null mice the resting heart rate was 10% lower than wild-type controls, while the resting mean arterial pressure was unchanged. During physical activity, the heart rate and blood pressure increased more in Brs3 null mice, reaching a similar heart rate and higher mean arterial pressure than control mice. When sympathetic input was blocked with propranolol, the heart rate of Brs3 null mice was unchanged, while the heart rate in control mice was reduced to the level of the null mice. The intrinsic heart rate, measured after both sympathetic and parasympathetic blockade, was similar in Brs3 null and control mice. Intravenous infusion of the BRS-3 agonist MK-5046 increased mean arterial pressure and heart rate in wild-type but not in Brs3 null mice, and this increase was blocked by pretreatment with clonidine, a sympatholytic, centrally acting ␣ 2-adrenergic agonist. In anesthetized mice, hypothalamic infusion of MK-5046 also increased both mean arterial pressure and heart rate. Taken together, these data demonstrate that BRS-3 contributes to resting cardiac sympathetic tone, but is not required for activity-induced increases in heart rate and blood pressure. The data suggest that BRS-3 activation increases heart rate and blood pressure via a central sympathetic mechanism.bombesin-like receptor 3; blood pressure; heart rate; sympathetic nervous system; energy metabolism NEW & NOTEWORTHY MK-5046, a bombesin-like receptor 3 (BRS-3) agonist, increases heart rate and blood pressure via increased central sympathetic tone. Brs3 null mice have a reduced resting heart rate that increases disproportionately with physical activity. BRS-3 contributes to the central regulation of heart rate and blood pressure.OBESITY is strongly associated with cardiovascular risk factors, including hypertension (6). However, the mechanisms linking obesity and hypertension are not fully understood (7,44). A number of neuroendocrine systems controlling energy homeostasis also regulate blood pressure and heart rate, including leptin, the melanocortin system, and ghrelin (12, 36, 45, 48 -50). The genetic and pharmacological manipulations of these systems that reduce adiposity generally also increase blood pressure, which is undesirable in a treatment for obesity.Bombesin-like receptor 3 (BRS-3) is a G protein-coupled receptor for which the endogenous ligand is unidentified (4,21,29,33). Despite the name, BRS-3 has a low affinity for bombesin and the related molecules, neuromedin B and gastrin-releasing ...