Thyroid Hormone and Insulin Metabolic Actions on Energy and Glucose Homeostasis

Faced with an environment of constantly changing nutrient availability, mammals have adapted complex homeostatic mechanisms to maintain energy balance. Deviations from this balance are largely corrected through a concerted, multi-organ effort that integrates hormonal signals with transcriptional regulatory networks. When these relationships are altered, as with over-nutrition and insulin resistance, metabolic disease ensues. Here, I present data concerning two distinct transcriptional pathways---one for thyroid hormone (TH) and one for insulin---that confer hormone responsiveness on metabolic gene programs that preserve energy homeostasis.;In brown adipose tissue (BAT), localized amplification of TH signaling by type 2 deiodinase (D2) is necessary for the acute thermogenic response to cold. Using mice lacking D2 (D2KO), we show that absence of D2-medaited TH signaling during BAT development decreases expression of the transcriptional program that defines BAT identity and underlies the thermogenic defects found in these mice in adulthood. Further, differentiation of D2KO brown adipocytes in vitro uncovered defective adipogenesis and decreased oxidative capacity consequent to enhanced oxidative stress and reduced insulin signaling. We hypothesized that impaired thermogenic potential of D2KO brown adipocytes alters metabolic response to high-fat feeding. Indeed, at thermoneutrality, D2KO mice exhibit increased susceptibility to obesity with glucose intolerance and hepatic steatosis. Interestingly, this phenotype was masked under room temperature thermal stress due to compensatory elevation of D2KO BAT sympathetic signaling. These discoveries highlight the importance of local activation of TH signaling in BAT development and function, with significant ramifications for diet-induced thermogenesis and energy homeostasis control.;When nutrients and insulin signaling are low, hepatic forkhead transcription factor FoxO1 maintains glucose homeostasis by inducing expression of gluconeogenic enzymes. In an effort to understand posttranslational modifications that alter FoxO1 activity, we identified deubiquitinating enzyme USP7. We show that USP7-mediated mono-deubiquitination of FoxO1 suppresses FoxO1 transcriptional activity by decreasing gene promoter occupancy. Knockdown of USP7 in hepatocytes elevated gluconeogenic genes in a FoxO1-dependent manner. Conversely, overexpression of USP7 suppressed gluconeogenic gene expression in hepatocyte cells and in mouse liver, decreasing hepatic glucose production. Insight into this pathway might aid in designing therapies to restore glucose metabolic control in those with type 2 diabetes.