FoxO1, the transcriptional chief of staff of energy metabolism

Abstract

FoxO1, one of the four FoxO isoforms of Forkhead transcription factors, is highly expressed in insulin-responsive tissues, including pancreas, liver, skeletal muscle and adipose tissue, as well as in the skeleton. In all these tissues FoxO1 orchestrates the transcriptional cascades regulating glucose metabolism. Indeed, FoxO1 is a major target of insulin which inhibits its transcriptional activity via nuclear exclusion. In the pancreas, FoxO1 regulates β-cell formation and function by a balanced dual mode of action that suppresses β-cell proliferation but promotes survival. Hepatic glucose production is promoted and lipid metabolism is regulated by FoxO1 such that under insulin resistance they lead to hyperglycemia and dyslipidemia, two features of type 2 diabetes. In skeletal muscle FoxO1 maintains energy homeostasis during fasting and provides energy supply through breakdown of carbohydrates, a process that leads to atrophy and underlies glycemic control in insulin resistance. In a dual function, FoxO1 regulates energy and nutrient homeostasis through energy storage in white adipose tissue, but promotes energy expenditure in brown adipose tissue. In its most recently discovered novel role, FoxO1 acts as a transcriptional link between the skeleton and pancreas as well as other insulin target tissues to regulate energy homeostasis. Through its expression in osteoblasts it controls glucose metabolism, insulin sensitivity and energy expenditure. In a feedback mode of regulation, FoxO1 is also a target of insulin signaling in osteoblasts. Insulin suppresses activity of osteoblastic FoxO1 thus promoting beneficial effects of osteoblasts on glucose metabolism. The multiple actions of FoxO1 in all glucose-regulating organs, along with clinical studies suggesting that its glycemic properties are conserved in humans, establish this transcription factor as a master regulator of energy metabolism across species.

Figure 1. FoxO1 is a unifying regulator of energy metabolism through the skeleton and peripheral organs

FoxO1 promotes glucose production by suppressing β-cell proliferation and insulin synthesis, by suppressing insulin sensitivity in the liver and white adipose tissue and by inducing expression of gluconeogenic enzymes. In the muscle, FoxO1 inhibits myoblastic differentiation but provides energy, when supplies are low, through breaking down of muscle protein leading to muscle atrophy. In white and brown adipose tissue FoxO1 has a dual function: in the first it decreases insulin sensitivity and suppresses adipogenesis and adipocyte size thus regulating energy and controlling energy storage. In the latter it decreases energy expenditure. In bone FoxO1 acts on osteoblasts to suppress expression of Esp and promote carboxylation/inactivation of Osteocalcin (OCN). Glucose levels increase through suppression of insulin production, decreased insulin sensitivity in the liver, muscle and white adipose tissue and suppression of energy expenditure. Although it decreases mitochondrial activity in the muscle, it is presently unknown whether if affects lean mass.