melanotan 2

Male C57BL/6J mice received bilateral nucleus accumbens microinjections of melanotan-II (0.1, 0.3, 1 nmol) and were tested in home cage and operant food self-administration paradigms. MT-II significantly decreased food consumption in both settings and reduced appetitive responding to gain access to food in a dose-dependent manner. No conditioned taste avoidance developed and metabolic parameters remained unchanged at anorexic doses. Results suggest melanocortin signaling in the ventral striatum selectively modulates appetite and satiety mechanisms without inducing aversive states or affecting basal metabolism

Site-specific microinjections of melanotan-II (0.025, 0.05, 0.075 nmol) and specific MC4-R agonist (0.024 nmol) into the subzona incerta of Siberian hamsters significantly increased interscapular brown adipose tissue temperature, with effects blocked by MC4R antagonist HS024. Immunohistochemical characterization revealed neurons and fibers positive for melanin concentrating hormone, oxytocin, vasopressin, agouti-related protein, and α-MSH. Study identifies a previously unreported brain region with high MC4-R mRNA co-localization with sympathetic outflow neurons to BAT that controls thermogenesis.

Female PACAP-/- and PACAP+/+ mice received daily peripheral melanotan-II injections for 3 weeks during cold acclimation. MTII partially rescued the impaired thermogenic capacity in PACAP-/- mice as measured by noradrenaline-induced metabolic rate. Treatment corrected the previously identified deficit in lipid utilization in response to adrenergic stimulation in PACAP-/- mice. Results provide physiological evidence that PACAP acts upstream of melanocortin receptors to facilitate sympathetically-induced mechanisms of adaptive thermogenesis in response to cold exposure.

Male Siberian hamsters received single third ventricular injection of melanotan-II or saline, with adipose tissue analyzed at 0.5, 1, and 2 hours post-injection. MTII significantly increased ratios of phosphorylated perilipin A and phosphorylated hormone-sensitive lipase in inguinal white adipose tissue at all timepoints and in interscapular brown adipose tissue at 30 minutes. Results demonstrate for the first time in rodents that phosphorylated perilipin A can serve as an in vivo, fat pad-specific indicator of lipolysis, extending previous findings that central melanocortin stimulation increases white adipose tissue lipolysis.

Study combined in situ hybridization for MC4-R mRNA with pseudorabies virus tract tracing injected into interscapular brown adipose tissue of Siberian hamsters. Significant numbers of double-labeled cells for PRV and MC4-R mRNA were found across the neuroaxis (mean ~60%), including hypothalamic paraventricular nucleus (~80%). Acute parenchymal MTII microinjections into PVH (0.05-0.075 nmol) increased IBAT temperature for up to 4 hours in awake, freely-moving hamsters. Data provide direct neuroanatomical and functional evidence that central melanocortins control IBAT thermogenesis via sympathetic innervation, likely through MC4 receptors.

MT-II-treated high-fat diet-induced obese mice lost weight and body fat, while MT-II-treated low-fat-fed mice maintained original body weight. Treatment led to general reduction in both visceral and subcutaneous adipose tissue in high-fat-fed mice compared to ad libitum controls. Vehicle-treated pair-fed DIO mice lost equivalent body weight compared to MT-II-treated mice but retained more adipose tissue, showing reduction in visceral fat with no effect on subcutaneous fat. Results indicate peripheral MT-II treatment leads to weight loss affecting both visceral and subcutaneous fat compartments through mechanisms beyond reduced food intake alone.