BACKGROUND & AIMS The hepatocyte-derived hormone fibroblast growth factor 21 (FGF21) is a hormone-like regulator of metabolism. The NAD+-dependent deacetylase SIRT1 regulates fatty acid metabolism through multiple nutrient sensors. Hepatic overexpression of SIRT1 reduces steatosis and glucose intolerance in obese mice. We investigated mechanisms by which SIRT controls hepatic steatosis in mice. METHODS Mice with liver-specific disruption of Sirt1 (SIRT1 LKO mice) and their wild-type littermates (controls) were divided into groups that were placed on normal chow diets, fasted for 24 hrs, or fasted for 24 hrs and then fed for 6 hrs. Liver tissues were collected and analyzed by histologic, gene expression profile, and real-time PCR assays. Human HepG2 cells were incubated with pharmacologic activators of SIRT1 (resveratrol or SRT1720) and assessed by mitochondrial oxidation and immunoblot analyses. FGF21 was overexpressed in SIRT1 LKO mice using an adenoviral vector. Energy expenditure was assessed by indirect calorimetry. RESULTS Fasting induced lipid deposition in livers of control mice, but severe hepatic steatosis in SIRT1 LKO mice. Gene expression analysis showed that fasting upregulated FGF21 in livers of control, but not SIRT1 LKO mice. Decreased hepatic and circulating levels of FGF21 in fasted SIRT1 LKO mice were associated with reduced hepatic expression of genes involved in fatty acid oxidation and ketogenesis, and increased expression of genes that control lipogenesis, compared with fasted control mice. Resveratrol or SRT1720 each increased transcriptional activity of the FGF21 promoter (–2070/+117) and levels of FGF21 mRNA and protein in HepG2 cells. Surprisingly, SIRT1 LKO mice developed late-onset obesity with impaired whole-body energy expenditure. Hepatic overexpression of FGF21 in SIRT1 LKO mice increased expression of genes that regulate fatty acid oxidation, decreased fasting-induced steatosis, reduced obesity, increased energy expenditure, and promoted browning of white adipose tissue. CONCLUSION SIRT1-mediated activation of FGF21 prevents liver steatosis caused by fasting. This hepatocyte-derived endocrine signaling appears to regulate expression of genes that control a brown fat-like program in white adipose tissue, energy expenditure, and adiposity. Strategies to activate SIRT1 or FGF21 might be used to treat fatty liver disease and obesity.

These data suggest excess RAAS activation in relationship to visceral adiposity in HIV-infected patients that may independently contribute to insulin resistance. Mineralocorticoid blockade may have therapeutic potential to reduce metabolic complications in HIV-infected patients with increased visceral adiposity.

Background: All-trans-retinoic acid ameliorates glucose intolerance and insulin resistance in diabetes. Results: The gene transcription of hepatic Fgf21 and its metabolic effects on lipid oxidation, ketogenesis, and whole-body energy expenditure are up-regulated by RAR␤ activation. Conclusion: Hepatic RAR␤ stimulates FGF21 production via the RARE. Significance: The hepatic RAR-FGF21 axis is a potential druggable target for treating metabolic syndrome.

Our results demonstrate dysfunctional sc adipose tissue marked by reduced Dicer in relationship to the down-regulation of brown and beige fat-related genes in lipodystrophic HIV patients and may provide a novel mechanism for metabolic dysregulation. A strategy to increase browning of white adipose tissue may improve cardiometabolic health in HIV.

The use of the SUBA-itraconazole formulation was associated with more rapid attainment of therapeutic levels with less interpatient variability compared with conventional liquid itraconazole when used as IFI prophylaxis in allogeneic HSCT or intermediate-/high-IFI risk haematological malignancy patients.