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      Disproportionate Inhibition of Feeding in A y Mice by Certain Stressors: A Cautionary Note

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      S. Karger AG

      Melanocortin, Feeding, Stress, Agouti, Mice, Hypoglycemia

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          A study of the effects of insulin-induced hypoglycemia in the obese yellow agouti A<sup>y</sup> mouse was initiated to test the hypothesis that the central melanocortin pathways are required for a normal sympathetic response to hypoglycemia. An experimental protocol was performed in which young nonobese male mice were isolated and fasted beginning on day 1, then tested for glucose responses to insulin-induced hypoglycemia on day 2. Normal mice demonstrated the expected glucose rebound to hypoglycemia, exceeding baseline glucose levels by 2–3 times as a consequence of increased gluconeogenesis and glycogenolysis before returning to baseline levels. A<sup>y</sup> animals lacked the rebound, exhibiting instead a gradual restoration of baseline glucose levels. The results suggested a defective sympathetic response to hypoglycemia in the A<sup>y</sup> mouse. However, a more detailed analysis demonstrated that the lack of a hyperglycemic rebound was due to an acute inhibition of feeding specifically in the A<sup>y</sup> mouse, which resulted not from the hypoglycemia stressor, but rather from the stress of isolation. Handling and intraperitoneal administration of saline also specifically inhibited food intake in the A<sup>y</sup> but not the wild-type mouse, while restraint stress had an equivalent inhibitory effect on food intake on wild-type and A<sup>y</sup> mice. Since the A<sup>y</sup> mouse has defective hypothalamic melanocortin-4 receptor (MC4-R) signaling, these data imply that the central melanocortin pathway is necessary for regulating the effects of stress on feeding behavior. Furthermore, these data demonstrate the need for exercising extreme caution in designing experiments to analyze feeding behavior and metabolism in genetic or pharmacological models involving perturbation of the melanocortin system.

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          Most cited references 5

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          Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin.

          Pro-opiomelanocortin (POMC)-derived peptides (the melanocortins adrenocorticotropin, alpha-, beta- and gamma-melanocyte stimulating hormone; and the endogenous opioid beta-endorphin) have a diverse array of biological activities, including roles in pigmentation, adrenocortical function and regulation of energy stores, and in the immune system and the central and peripheral nervous systems. We show here that mice lacking the POMC-derived peptides have obesity, defective adrenal development and altered pigmentation. This phenotype is similar to that of the recently identified human POMC-deficient patients. When treated with a stable alpha-melanocyte-stimulating hormone agonist, mutant mice lost more than 40% of their excess weight after 2 weeks. Our results identify the POMC-null mutant mouse as a model for studying the human POMC-null syndrome, and indicate the therapeutic use of peripheral melanocortin in the treatment of obesity.
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            Antagonism of Central Melanocortin Receptors in Vitro and in Vivo by Agouti-Related Protein

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              Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides.

              Mutations reducing the functional activity of leptin, the leptin receptor, alpha-melanocyte stimulating hormones (alpha-MSH) and the melanocortin-4 receptor (Mc4r) all lead to obesity in mammals. Moreover, mutant mice that ectopically express either agouti (Ay/a mice) or agouti-related protein (Agrp), antagonists of melanocortin signalling, become obese. These data suggest that alpha-MSH signalling transduced by Mc4r tonically inhibits feeding; however, it is not known to what extent this pathway mediates leptin signalling. We show here that Mc4r-deficient (Mc4r-/-) mice do not respond to the anorectic actions of MTII, an MSH-like agonist, suggesting that alpha-MSH inhibits feeding primarily by activating Mc4r. Obese Mc4r-/-mice do not respond significantly to the inhibitory effects of leptin on feeding, whereas non-obese Mc4r-/- mice do. These data demonstrate that melanocortin signalling transduced by Mc4r is not an exclusive target of leptin action and that factors resulting from obesity contribute to leptin resistance. Leptin resistance of obese Mc4r-/- mice does not prevent their response to the anorectic actions of ciliary neurotrophic factor (CNTF), corticotropin releasing factor (CRF), or urocortin; or the orexigenic actions of neuropeptide Y (NPY) or peptide YY (PYY), indicating that these neuromodulators act independently or downstream of Mc4r signalling.

                Author and article information

                S. Karger AG
                August 2000
                07 September 2000
                : 72
                : 2
                : 126-132
                Vollum Institute, Oregon Health Sciences University, Portland, Oreg., USA
                54579 Neuroendocrinology 2000;72:126–132
                © 2000 S. Karger AG, Basel

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                Page count
                Figures: 6, References: 17, Pages: 7


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