Pro-opiomelanocortin (POMC)-derived peptides and the regulation of energy homeostasis.
Human genetic data indicate impaired synthesis or processing of POMC results in obesity. We have used a mouse model of POMC deficiency (Pomc null) to explore the role of POMC-derived peptides in energy homeostasis. The phenotype of Pomc null mice recapitulates the clinical syndrome seen in humans congenitally lacking POMC. Loss of only one copy of the Pomc gene is sufficient to render mice susceptible to the effects of high fat feeding, emphasizing an important gene-environment interaction predisposing to obesity. Our studies indicate that POMC-derived peptides have influences on the response to a high fat diet, including a major influence on the dietary preference for fat. Pomc null mice are unusual in that obesity and hyperphagia develop in the absence of circulating glucocorticoid (GC). To investigate the interaction between GCs and the melanocortin system, we administered corticosterone to Pomc null mice. They appear hypersensitive to the adverse metabolic effects of GCs, developing hypertension, an exacerbation of both hyperphagia and obesity and a profound insulin resistance. GC treatment of Pomc null mice significantly increases the expression of the melanocortin antagonist agouti-related protein (AgRP). On-going studies in mice lacking both AgRP and Pomc will determine whether the metabolic phenotype seen with this GC therapy is due to a lack of melanocortin peptide, the unopposed action of AgRP or a combination of both.
University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. apc36@cam.ac.uk
Anthony P
AP
Coll
Y C
YC
Loraine Tung
D000818:Animals; D004032:Diet; D004734:Energy Metabolism; D005502:Food; D005518:Food Preferences; D005938:Glucocorticoids / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D053486:Melanocortins / Q000378:metabolism; D009074:Melanocyte-Stimulating Hormones / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism
D005938:Glucocorticoids; D053486:Melanocortins; D010455:Peptides; D020033:Protein Isoforms; D011333:Pro-Opiomelanocortin; D009074:Melanocyte-Stimulating Hormones