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

Abstract

High-fat diet (HFD) triggers insulin resistance and diabetes mellitus, but their link remains unclear. Characterization of overt hyperglycemia in insulin receptor mutant (InsrP1195L/+) mice exposed to HFD (InsrP1195L/+/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 InsrP1195L/+/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 InsrP1195L/+/HFD liver. Among these, the expression of Cyp7a1, a BA synthesis enzyme, was insulin-dependent and was markedly decreased in InsrP1195L/+/HFD liver. Reduced Cyp7a1 expression in InsrP1195L/+/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 InsrP1195L/+/HFD liver.

<b>Importance of Hepatocyte Nuclear Factor 4α in Glycerol-induced Glucose-6-phosphatase Expression in </b><b>Liver </b>

“…Other substrates for glycolysis, such as glucose, might have similar effects on G6pc transcription. However, this appears not to be the case, since we previously found that glycerol and glucose evoke apparently different consequences on G6pc expression, when administered to mice in vivo (15). Our present study indicates that the DNA response element for HNF4α in the G6pc promoter is essential for its transactivation by glycerol and by oleate.…”

“…G6pc expression in the liver was shown to be increased in type 2 diabetes patients and to be correlated with increased hepatic glucose production (3). In addition, we found that increased G6pc expression is responsible for the hyperglycemia in a mouse model of type 2 diabetes mellitus (15). In the present study, we found that glycerol administration in vitro increased G6pc expression but not Pck1 expression in FAO cells, indicating that glycerol-induced G6pc transactivation is G6pc transcription (20).…”

“…We recently found that mice harboring a loss of function mutation in the insulin receptor (Insr P1195L/+ mice) develop marked hyperglycemia under high fat diet feeding (15). Our data showed that unsuppressed lipolysis and increased gluconeogenesis from glycerol contribute to the occurrence of hyperglycemia in these mice.…”

“…Accordingly, further studies are needed to clarify the involvement of PGC1-α or PPARγ/RXRα, as well as that of HNF4α, in glycerol-induced G6pc expression via the DNA response element for HNF4α in the G6pc promoter. We recently found that HFD-feeding of insulinresistant mice (Insr P1195L/+ mice) induces hyperglycemia associated with increased gluconeogenesis from glycerol and upregulation of G6pc expression on refeeding (15). Considering that unsuppressed gluconeogenesis contributes to the development of hyperglycemia in type 2 diabetes mellitus (23) in humans as well as in rodents, the elucidation of the molecular mechanism of glycerol-induced G6pc transcription would deepen our understanding of pathophysiology of diabetes mellitus and could lead to the development of novel approaches to treat type 2 diabetes mellitus.…”

Effects of Periconception Cadmium and Mercury Co-Administration to Mice on Indices of Chronic Diseases in Male Offspring at Maturity

“…Likewise, in the liver, transcript abundance for genes required for fatty acid uptake (FATP2 and CD36) and glucose homeostasis (G6PC) was analyzed in male offspring of control and treated females. Aberrant mRNA expression for these genes is positively correlated with insulin resistance and impaired glucose homeostasis (Ge et al 2010; Konstantynowicz-Nowicka et al 2015; Lee et al 2015) ( n = 11 for controls and n = 17 for treated offspring for both adipose and liver tissues; at the termination of the experiment, tissue samples were randomly chosen for molecular studies and all available samples were used).…”