Nonalcoholic fatty liver disease is closely associated with metabolic disorders, even in nonobese, nondiabetic subjects. Nonalcoholic fatty liver disease can be considered an early predictor of metabolic disorders, particularly in the normal-weight population.

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OBJECTIVES:We investigated the effect of obesity on the serum levels of total and free IGF-1 and their relationship to the circulating levels of insulin and IGF binding proteins (IGFBPs) in age and sex-matched groups. SUBJECTS: The study included 43 obese subjects (ideal body weight; IBW b 120%) and 45 controls (IBW`100%). All of the subjects were male. MEASUREMENT: Total IGF-1, free IGF-1, IGFBP-1, IGFBP-2, IGFBP-3, and insulin were measured in obese subjects and normal control subjects. RESULTS: No signi®cant differences in the circulating levels of total and IGFBP-3 were observed between the obese and control groups. In contrast to total IGF-1, free IGF-1 in obese subjects was signi®cantly increased compared to normal controls (P`0.05). Serum total and free IGF-1 were inversely correlated with age (r À0.42, P 0.001, and À0.44, P 0.001). Fasting serum insulin concentrations were elevated in all the obese subjects (P`0.05) and positively correlated with IBW (r 0.57, P 0.001). The levels of serum GH and IGFBP-1 were suppressed in all the obese subjects (P`0.05). IGFBP-1 was inversely correlated with IBW (r À0.51, P 0.001) and serum insulin concentrations (r À0.48, P 0.001). The IGFBP-2 concentrations were also suppressed in obese subjects and inversely related to free IGF-1 (r À0.48, P 0.001). Using multiple linear regression analysis, total IGF-1 and insulin concentrations were positively correlated (r 0.58, P 0.001) and free IGF-1 and IGFBP-1 concentrations were negatively correlated (r À0.57, P 0.001). CONCLUSION: We con®rmed that total IGF-1 and IGFBP-3 concentrations were not signi®cantly different between the obese and control groups, despite GH hyposecretion in obesity. We also found that free IGF-1 concentrations were higher in obese subjects than in normal controls. It seems likely that overnutrition and chronic hyperinsulinaemia in obesity may alter this regulated growth response by insulin stimulation of IGF-1 production and suppression of hepatic IGFBP-1 and IGFBP-2 production, which may inhibit IGF-1 bioactivity.

(2015) Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway, Autophagy, 11:1, 46-59, DOI: 10.4161/15548627.2014 Abbreviations: 3MA, 3-methyladenine; CQ, chloroquine; CR, caloric restriction; GOT1/AST, glutamic-oxaloacetic transaminase 1, soluble; GPT/ALT, glutamic-pyruvate transaminase (alanine aminotransferase); IPGTTs, intraperitoneal glucose tolerance tests; Met, metformin; MTOR, mechanistic target of rapamycin; NAFLD, nonalcoholic fatty liver disease; OA, oleic acid; ORO, Oil Red O; PRKA, protein kinase, AMP-activated; siRNA, short interfering RNA; SIRT1, sirtuin 1; T-CHO, total cholesterol; TG, triglyceride.Metformin activates both PRKA and SIRT1. Furthermore, autophagy is induced by either the PRKA-MTOR-ULK1 or SIRT1-FOXO signaling pathways. We aimed to elucidate the mechanism by which metformin alleviates hepatosteatosis by examining the molecular interplay between SIRT1, PRKA, and autophagy. ob/ob mice were divided into 3 groups: one with ad libitum feeding of a standard chow diet, one with 300 mg/kg intraperitoneal metformin injections, and one with 3 g/d caloric restriction (CR) for a period of 4 wk. Primary hepatocytes or HepG2 cells were treated with oleic acid (OA) plus high glucose in the absence or presence of metformin. Both CR and metformin significantly improved body weight and glucose homeostasis, along with hepatic steatosis, in ob/ob mice. Furthermore, CR and metformin both upregulated SIRT1 expression and also stimulated autophagy induction and flux in vivo. Metformin also prevented OA with high glucose-induced suppression of both SIRT1 expression and SIRT1-dependent activation of autophagy machinery, thereby alleviating intracellular lipid accumulation in vitro. Interestingly, metformin treatment upregulated SIRT1 expression and activated PRKA even after siRNA-mediated knockdown of PRKAA1/2 and SIRT1, respectively. Taken together, these results suggest that metformin alleviates hepatic steatosis through PRKA-independent, SIRT1-mediated effects on the autophagy machinery.