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Dynorphin Knockout Reduces Fat Mass and Increases Weight Loss during Fasting in Mice

Neuroscience Program (A.S., S.L., K.M., K.S., N.J.L., D.B., C.S., T.K., E.-J.D.L., M.C., H.H.) and Bone and Mineral Research Program (R.E., P.B.), Garvan Institute of Medical Research, St. Vincent’s Hospital, Darlinghurst, Sydney, New South Wales 2010, Australia; Bioanalytical Mass Spectrometry Facility (G.A.S.), Faculty of Medicine, University of New South Wales, Randwick, New South Wales 2052, Australia; Department of Pharmacology (C.S.), Innsbruck Medical University, A-6020 Innsbruck, Austria; and Neuroscience Institute of Schizophrenia and Allied Disorders (T.K.), Darlinghurst, Sydney, New South Wales 2010, Australia

Address all correspondence and requests for reprints to: Amanda Sainsbury, Neuroscience Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia. E-mail: a.sainsbury-salis{at}garvan.org.au.

Endogenous opioids, particularly dynorphins, have been implicated in regulation of energy balance, but it is not known how they mediate this in vivo. We investigated energy homeostasis in dynorphin knockout mice (Dyn^–/– mice) and probed the interactions between dynorphins and the neuropeptide Y (NPY) system. Dyn^–/– mice were no different from wild types with regards to body weight and basal and fasting-induced food intake, but fecal output was increased, suggesting decreased nutrient absorption, and they had significantly less white fat and lost more weight during a 24-h fast. The neuroendocrine and thermal responses to fasting were at least as pronounced in Dyn^–/– as in wild types, and there was no stimulatory effect of dynorphin knockout on 24-h energy expenditure (kilocalories of heat produced) or physical activity. However, Dyn^–/– mice showed increased circulating concentrations of 3,4-dihydroxyphenlacetic acid and 3,4-dihydroxyphenylglycol, suggesting increased activity of the sympathetic nervous system. The respiratory exchange ratio of male but not female Dyn^–/– mice was reduced, demonstrating increased fat oxidation. Interestingly, expression of the orexigenic acting NPY in the hypothalamic arcuate nucleus was reduced in Dyn^–/– mice. However, fasting-induced increases in pre-prodynorphin expression in the arcuate nucleus, the paraventricular nucleus, and the ventromedial hypothalamus but not the lateral hypothalamus were abolished by deletion of Y₁ but not Y₂ receptors. Therefore, ablation of dynorphins results in increases in fatty acid oxidation in male mice, reductions in adiposity, and increased weight loss during fasting, possibly via increases in sympathetic activity, decreases in intestinal nutrient absorption, and interactions with the NPYergic system.

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