Hepatic insulin signaling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expression.

Dissecting the role of insulin in the complex regulation of triglyceride metabolism is necessary for understanding dyslipidemia and steatosis. Liver insulin receptor knockout (LIRKO) mice show that in the physiological context of feeding, hepatic insulin signaling is not required for the induction of mTORC1, an upstream activator of the lipogenic regulator, SREBP-1c. Feeding induces SREBP-1c mRNA in LIRKO livers, though not to the extent observed in controls. A high fructose diet also partially induces SREBP-1c and lipogenic gene expression in LIRKO livers. Insulin signaling becomes more important in the pathological context of obesity, as knockdown of the insulin receptor in ob/ob mice, a model of Type 2 diabetes, using antisense oligonucleotides, abolishes the induction of SREBP-1c and its targets by obesity and ameliorates steatosis. Thus, insulin-independent signaling pathways can partially compensate for insulin in the induction of SREBP-1c by feeding but the further induction by obesity/Type 2 diabetes is entirely dependent upon insulin.