[Show abstract][Hide abstract] ABSTRACT: Genetic1,
8 and pharmacological6,
studies have defined a role for the melanocortin-4 receptor (Mc4r) in the
regulation of energy homeostasis. The physiological function of Mc3r, a melanocortin
receptor expressed at high levels in the hypothalamus13, has
remained unknown. We evaluated the potential role of Mc3r in energy homeostasis
by studying Mc3r-deficient (Mc3r
and compared the functions of Mc3r and Mc4r in mice deficient
for both genes. The 4−6-month Mc3r
mice have increased fat mass, reduced lean mass and higher feed efficiency
than wild-type littermates, despite being hypophagic and maintaining normal
metabolic rates. (Feed efficiency is the ratio of weight gain to food intake.)
Consistent with increased fat mass, Mc3r
mice are hyperleptinaemic and male Mc3r
mice develop mild hyperinsulinaemia. Mc3r
mice did not have significantly altered corticosterone or total thyroxine
(T4) levels. Mice lacking both Mc3r and Mc4r become significantly
heavier than Mc4r
-/- mice. We conclude that
Mc3r and Mc4r serve non-redundant roles in the regulation of energy homeostasis.
[Show abstract][Hide abstract] ABSTRACT: MTII, an agonist of melanocortinergic receptors, is a well-documented anorexigenic agent in rats. Many investigators have reported its effects on feeding without considering concurrent alterations in other behaviors. Accordingly, we performed studies to simultaneously measure nocturnal feeding, drinking, activity, and temperature of rats after intracerebroventricular (third ventricle) administration of a wide dose range of MTII (0.05-500 ng). We observed that MTII modulates these physiological parameters in a dose-dependent manner. Low doses of MTII (0.05 ng) caused reductions in feeding without alterations in body temperature, drinking, or activity. In contrast, hyperthermia and disrupted drinking patterns, along with food intake reductions, were evident at doses exceeding 50 ng. The fact that low doses altered only feeding, whereas higher doses affected a range of parameters, suggests that certain melanocortin-induced behavioral changes may be mediated by distinct populations of melanocortin receptors with varying affinities or that those changes seen at higher doses may be nonspecific in nature.
Journal of Applied Physiology 08/2000; 89(1):273-82. · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Transgenic Research 03/2000; 9(2):145-154. · 2.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine whether the deletion of stromelysin-1, a single metalloproteinase gene product, will alter the time course and quality of dermal wound repair in mice.
After dermal injury, a highly coordinated program of events is initiated by formation of a fibrin clot, followed by migration of keratinocytes, contraction of the dermis, recruitment of inflammatory macrophages, formation of granulation tissue with angiogenesis, and finally tissue remodeling. Matrix metalloproteinases are rapidly induced in the dermis and granulation tissue and at the leading edge of the epidermis in the healing wounds.
Incisional and circular full-thickness wounds 2 to 10 mm were made in the dermis of stromelysin-1-deficient and wild-type mice. The wounds were analyzed for rate of cellular migration and epithelialization. The wound contraction was examined by immunohistochemical staining for alpha-smooth muscle actin and fluorescent staining for fibrillar actin.
Independent of the age of the animal, excisional wounds in stromelysin-1-deficient mice failed to contract and healed more slowly than those in wild-type mice. Cellular migration and epithelialization were unaffected in the stromelysin-1-deficient animals. The functional defect in these mice is failure of contraction during the first phase of healing because of inadequate organization of actin-rich stromal fibroblasts.
Excisional dermal wound healing is impaired in mice with a targeted deletion in the stromelysin-1 gene. Incisional wound healing is not affected. These data implicate stromelysin-1 proteolysis during early wound contraction and indicate that stromelysin-1 is crucial for the organization of a multicellular actin network.
Annals of Surgery 09/1999; 230(2):260-5. · 7.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Melanocortinergic neurons are believed to play a role in the control of food intake. Melanocortin receptor agonists and antagonists modulate feeding in several mouse models of chemically and genetically induced hyperphagia. To date, little information is available describing the role of this neurological system in the control of the natural feeding cycle in genetically intact rats. To evaluate the involvement of melanocortins in spontaneous nocturnal feeding, the synthetic melanocortin receptor agonist, MTII and the antagonist, SHU9119 were administered ICV (third ventricle) alone and in combination. Dose-dependent inhibition or stimulation of food intake was observed with MTII or SHU9119, respectively. Co-injections containing equal concentrations of MTII and SHU9119 resulted in food intake that was indistinguishable from controls. Food intake patterns observed in studies in which various dose combinations of MTII and SHU9119 were co-injected are consistent with the concept that both affect feeding by acting on similar melanocortin receptors. The hypothesis that effects of melanocortins on feeding may be mediated via an NPY related pathway was tested by co-injecting MTII and NPY in a 2-h satiated food intake paradigm. MTII inhibited food intake induced by 5.0 microg hNPY in a dose dependent manner with the highest dose tested abolishing the NPY feeding response. The studies suggest that melanocortins act via specific receptors to control food intake in rats, possibly via an NPY related pathway. If similar neurochemical processes operate in humans, selectively modulating specific melanocortin receptor signaling may be an approach to the treatment of human obesity.
[Show abstract][Hide abstract] ABSTRACT: A procedure is described for gram-scale refolding of Escherichia coli-derived human leptin inclusion bodies. Refolding was achieved by gradually reducing denaturant using a diafiltration method. Refolded leptin is characterized by in vivo modulation of food intake, reduction in body weight, and lowering of insulin and glucose levels in ob/ob mice. In addition, refolded leptin is characterized by radioimmunoassay (RIA) and activation of the leptin receptor in a cell-based assay. For comparison we also refolded leptin by a simple dilution method and produced periplasmic derived leptin, which did not require ex vivo folding. Leptin produced by these three methods and leptin obtained from commercial sources were compared using the RIA and the cell-based assay and appeared to be of comparable quality and potency.
Protein Expression and Purification 01/1999; 14(3):335-42. · 1.51 Impact Factor