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High-fat diet (HFD) triggers insulin resistance and diabetes mellitus, but their link remains unclear. Characterization of overt hyperglycemia in insulin receptor mutant ( Insr   P1195L/ + ) mice exposed to HFD ( Insr   P1195L/ + /HFD mice) revealed increased glucose-6-phosphatase ( G6pc ) expression in liver and increased gluconeogenesis from glycerol. Lipolysis in white adipose tissues (WAT) and lipolysis-induced blood glucose rise were increased in  Insr   P1195L/ + /HFD mice, while wild-type WAT transplantation ameliorated the hyperglycemia and the increased  G6pc  expression. We found that the expressions of genes involved in bile acid (BA) metabolism were altered in  Insr   P1195L/ + /HFD liver. Among these, the expression of Cyp7a1, a BA synthesis enzyme, was insulin-dependent and was markedly decreased in  Insr   P1195L/ + /HFD liver. Reduced  Cyp7a1  expression in  Insr   P1195L/ + /HFD liver was rescued by WAT transplantation, and the expression of  Cyp7a1  was suppressed by glycerol administration in wild-type liver. These findings suggest that unsuppressed lipolysis in adipocytes elicited by HFD feeding is linked with enhanced gluconeogenesis from glycerol and with alterations in BA physiology in  Insr   P1195L/ + /HFD liver.

Unsuppressed lipolysis in adipocytes is linked with enhanced gluconeogenesis and altered bile acid physiology in InsrP1195L/+ mice fed high-fat-diet