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Deletion of the RIIß-Subunit of Protein Kinase A Decreases Body Weight and Increases Energy Expenditure in the Obese, Leptin-Deficient ob/ob Mouse

Department of Pharmacology (K.J.N, G.S.M.), University of Washington, and Division of Metabolism (D.E.C.), Endocrinology and Nutrition, University of Washington, Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98195; and Wyeth Research (M.A.N.), Collegeville, Pennsylvania 19426

Address all correspondence and requests for reprints to: Dr. G. Stanley McKnight, Department of Pharmacology, University of Washington, Box 357750, Seattle, Washington 98195. E-mail: mcknight{at}u.washington.edu.

Disruption of the RIIß regulatory subunit of protein kinase A (PKA) results in mice with a lean phenotype, nocturnal hyperactivity, and increased resting metabolic rate. In this report, we have examined whether deletion of RIIß would lead to increased metabolism and rescue the obese phenotype of the leptin-deficient ob/ob (ob) mouse. Body weight gain and food consumption were decreased, whereas basal oxygen consumption and nocturnal locomotor activity were increased in the double mutant animals compared with ob mice. The ob mice are unable to maintain body temperature when placed in a cold environment due to a loss of brown adipose tissue activation, and this cold sensitivity was partially rescued by concomitant disruption of RIIß. These findings indicate that PKA modifies the phenotype of the leptin-deficient mouse, leading to increases in both thermogenesis and energy expenditure.

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