Abstract
The nutrient-sensing mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway controls cellular and organismal growth and metabolism, while aberrant activation is linked to human disease, including metabolic disease. Cellular studies have established several regulatory mechanisms influencing mTORC1 activation, but the physiological signals that control mTORC1 at the organismal and tissue levels are less well defined. mTORC1 is dynamically regulated by fasting and feeding in metabolic tissues, with both nutrients and insulin proposed to activate mTORC1 in response to feeding. Here, a liver-specific mouse model that disconnects mTORC1 activation from AKT-mediated TSC2 phosphorylation is employed. This genetic mouse model demonstrates that AKT-mediated TSC2 phosphorylation is the predominant mechanism of hepatic mTORC1 induction by insulin but is dispensable for activation by feeding. Furthermore, dietary protein is critical and dictates the insulin-responsiveness of hepatic mTORC1 signaling. Contrary to dogma, hepatic mTORC1 signaling was not elevated in response to diet-induced obesity associated with the phenotypes of type-2 diabetes, including hyperinsulinemia, systemic insulin resistance, and hyperglycemia, and blocking hepatic AKT-TSC-mTORC1 signaling did not prevent these metabolic impairments. Evidence is also provided supporting a role for glucagon in hepatic mTORC1 suppression during fasting. This study reveals a hierarchy of physiological signals regulating hepatic mTORC1.