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Increased Serum Leptin Protects From Adiposity Despite the Increased Glucose Uptake in White Adipose Tissue in Mice Lacking p85 Phosphoinositide 3-Kinase

¹ Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
² Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Kawaguchi, Japan
³ National Institute of Health and Nutrition, Tokyo, Japan
⁴ Division of Laboratory Animal Science, Animal Research Center, Tokyo Medical University, Tokyo, Japan
⁵ Laboratory for Vertebrate Body Plan, Center for Developmental Biology, RIKEN, Kobe, Japan
⁶ Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo, Japan
⁷ Department of Physiological Chemistry, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan

Mice lacking the p85 regulatory subunit of phosphoinositide (PI) 3-kinase (Pik3r1^–/–) showed increased glucose uptake in white adipose tissue (WAT) and skeletal muscle due to increased phosphatidylinositol (3,4,5)-triphosphate [PtdIns(3,4,5)P3] production and on a normal diet had a body weight and fat mass similar to wild-type mice. After 3 months on a high-fat diet, Pik3r1^–/– mice still had increased insulin sensitivity and better glucose tolerance than wild-type mice, but showed markedly greater increases in body weight and WAT mass than wild-type mice. On the normal diet, serum leptin levels of Pik3r1^–/– mice were significantly higher than in wild-type mice as a result of increased leptin secretion from adipocytes, presumably due to the increased PtdIns(3,4,5)P3 production in adipocytes. Leptin (5 µg/g body wt per day) caused a reduction in food intake and decrease in body weight by the wild-type mice as well as Pik3r1^–/– mice, suggesting Pik3r1^–/– mice having leptin sensitivity similar to wild-type mice. The slightly increased serum leptin compensated for the increased glucose uptake by adipocytes in Pik3r1^–/– mice, thereby preventing adiposity on the normal diet. On the high-fat diet, leptin (5 µg/g body wt per day) failed to decrease food intake or body weight in either genotype, indicating that both genotypes had indeed become severely leptin resistant. Consequently, leptin secretion was unable to sufficiently compensate for the severe leptin resistance caused by the high-fat diet, thereby failing to prevent obesity in Pik3r1^–/– mice. Our findings suggest that primary increase in serum leptin on the normal diet play a role in the protection from adiposity in Pik3r1^–/– mice.

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