RESUMO
The hepatic transcription factor forkhead box O1 (FOXO1) is a critical regulator of hepatic and systemic insulin sensitivity. Previous work by our group and others demonstrated that genetic inhibition of FOXO1 improves insulin sensitivity both in genetic and dietary mouse models of metabolic disease. Mechanistically, this is due in part to cell nonautonomous control of adipose tissue insulin sensitivity. However, the mechanisms mediating this liver-adipose tissue crosstalk remain ill defined. One candidate hepatokine controlled by hepatic FOXO1 is fibroblast growth factor 21 (FGF21). Preclinical and clinical studies have explored the potential of pharmacological FGF21 as an antiobesity and antidiabetic therapy. In this manuscript, we performed acute loss-of-function experiments to determine the role of hepatocyte-derived FGF21 in glucose homeostasis and insulin tolerance both in control and mice lacking hepatic insulin signaling. Surprisingly, acute deletion of FGF21 did not alter glucose tolerance, insulin tolerance, or adipocyte lipolysis in either liver-specific FGF21KO mice or mice lacking hepatic AKT-FOXO1-FGF21, suggesting a permissive role for endogenous FGF21 in the regulation of systemic glucose homeostasis and insulin tolerance in mice. In addition, these data indicate that liver FOXO1 controls glucose homeostasis independently of liver-derived FGF21.
Assuntos
Resistência à Insulina , Lipólise , Animais , Fatores de Crescimento de Fibroblastos/metabolismo , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Glucose/metabolismo , Homeostase/genética , Insulina/metabolismo , Resistência à Insulina/genética , Lipólise/genética , Fígado/metabolismo , Camundongos , Camundongos KnockoutRESUMO
The insulin responsive Akt and FoxO1 signaling axis is a key regulator of the hepatic transcriptional response to nutrient intake. Here, we used global run-on sequencing (GRO-seq) to measure the nascent transcriptional response to fasting and refeeding as well as define the specific role of hepatic Akt and FoxO1 signaling in mediating this response. We identified 599 feeding-regulated transcripts, as well as over 6,000 eRNAs, and mapped their dependency on Akt and FoxO1 signaling. Further, we identified several feeding-regulated lncRNAs, including the lncRNA Gm11967, whose expression was dependent upon the liver Akt-FoxO1 axis. Restoring Gm11967 expression in mice lacking liver Akt improved insulin sensitivity and induced glucokinase protein expression, indicating that Akt-dependent control of Gm11967 contributes to the translational control of glucokinase. More broadly, we have generated a unique genome-wide dataset that defines the feeding and Akt/FoxO1-dependent transcriptional changes in response to nutrient availability.
RESUMO
Organismal stressors such as cold exposure require a systemic response to maintain body temperature. Brown adipose tissue (BAT) is a key thermogenic tissue in mammals that protects against hypothermia in response to cold exposure. Defining the complex interplay of multiple organ systems in this response is fundamental to our understanding of adipose tissue thermogenesis. In this study, we identify a role for hepatic insulin signaling via AKT in the adaptive response to cold stress and show that liver AKT is an essential cell-nonautonomous regulator of adipocyte lipolysis and BAT function. Mechanistically, inhibition of forkhead box O1 (FOXO1) by AKT controls BAT thermogenesis by enhancing catecholamine-induced lipolysis in the white adipose tissue (WAT) and increasing circulating fibroblast growth factor 21 (FGF21). Our data identify a role for hepatic insulin signaling via the AKT-FOXO1 axis in regulating WAT lipolysis, promoting BAT thermogenic capacity, and ensuring a proper thermogenic response to acute cold exposure.