FoxO1 Is Required for Most of the Metabolic and Hormonal Perturbations Produced by Hepatic Insulin Receptor Deletion in Male Mice.

Insulin coordinates the complex response to feeding, affecting numerous metabolic and hormonal pathways. Forkhead box protein O1 (FoxO1) is one of several signaling molecules downstream of insulin; FoxO1 drives gluconeogenesis and is suppressed by insulin. To determine the role of FoxO1 in mediating other actions of insulin, we studied mice with hepatic deletion of the insulin receptor, FoxO1, or both. We found that mice with deletion of the insulin receptor alone showed not only hyperglycemia but also a 70% decrease in plasma insulin-like growth factor 1 and delayed growth during the first 2 months of life, a 24-fold increase in the soluble leptin receptor and a 19-fold increase in plasma leptin levels. Deletion of the insulin receptor also produced derangements in fatty acid metabolism, with a decrease in the expression of the lipogenic enzymes, hepatic diglycerides, and plasma triglycerides; in parallel, it increased expression of the fatty acid oxidation enzymes. Mice with deletion of both insulin receptor and FoxO1 showed a much more modest phenotype, with normal or near-normal glucose levels, growth, leptin levels, hepatic diglycerides, and fatty acid oxidation gene expression; however, lipogenic gene expression remained low. Taken together, these data reveal the pervasive role of FoxO1 in mediating the effects of insulin on not only glucose metabolism but also other hormonal signaling pathways and even some aspects of lipid metabolism.

Mice lacking lipid droplet-associated hydrolase, a gene linked to human prostate cancer, have normal cholesterol ester metabolism.

Variations in the gene LDAH (C2ORF43), which encodes lipid droplet-associated hydrolase (LDAH), are among few loci associated with human prostate cancer. Homologs of LDAH have been identified as proteins of lipid droplets (LDs). LDs are cellular organelles that store neutral lipids, such as triacylglycerols and sterol esters, as precursors for membrane components and as reservoirs of metabolic energy. LDAH is reported to hydrolyze cholesterol esters and to be important in macrophage cholesterol ester metabolism. Here, we confirm that LDAH is localized to LDs in several model systems. We generated a murine model in which Ldah is disrupted but found no evidence for a major function of LDAH in cholesterol ester or triacylglycerol metabolism in vivo, nor a role in energy or glucose metabolism. Our data suggest that LDAH is not a major cholesterol ester hydrolase, and an alternative metabolic function may be responsible for its possible effect on development of prostate cancer.