Weight Loss Induced by Bariatric Surgery Restricts Hepatic GDF15 Expression

Abstract

Introduction: Obesity and related nonalcoholic fatty liver disease (NAFLD) are an emerging health care issue that imposes substantial morbidity to individuals. Growth and differentiation factor 15 (GDF15) limits food uptake, body weight, and energy balance by modulation of GDNF-family receptor α-like (GFRAL) signalling in the hindbrain. However, the regulation of GDF15 expression in obesity and NAFLD is incompletely understood. We sought to define the impact of weight loss achieved by laparoscopic adjustable gastric banding (LAGB) on hepatic and adipose GDF15 expression in a cohort of severely obese patients.

Methods: We analysed GDF15 expression of liver and subcutaneous adipose tissue before and 6 months after LAGB in severely obese patients undergoing LAGB by quantitative real-time PCR. To assess the role of inflammation on GDF15 expression, we analysed Hep G2 hepatocytes stimulated with cytokines such as IL-1β, TNFα, IL-6, LPS, or cellular stressors such as tunicamycin.

Results: GDF15 expression was mostly confined to the liver compared to adipose tissue in severely obese patients. Weight loss induced by LAGB was associated with reduced hepatic (but not adipose tissue) expression of GDF15. Stimulation with IL-1β or tunicamycin induced hepatic GDF15 expression in hepatocytes. In line with this, hepatic GDF15 expression directly correlated with IL-1β expression and steatosis severity in NAFLD. These data demonstrated that amelioration of metabolic inflammation and weight loss reduced hepatic GDF15 expression.

Conclusion: Based on recent mechanistic findings, our data suggest that hepatic GDF15 may serve as a negative feedback mechanism to control energy balance in NAFLD.

Figure 1

GDF15 is strongly expressed in the liver of obese subjects and decreases after laparoscopic adjustable gastric banding. (a) Hepatic and subcutaneous adipose tissue GDF15 expression in obese patients determined by qPCR and normalised to GAPDH. (b, c) Hepatic (b) and subcutaneous adipose tissue (c) GDF15 expression in obese patients before and 6 months after LAGB determined by qPCR and normalised to GAPDH. ^∗ P < 0.05, ^∗∗ P < 0.01.

Figure 2

IL-1β and tunicamycin promote GDF15 expression in hepatocytes. (a, b) GDF15 expression in Hep G2 hepatocytes over the course of 48 hours stimulation with interleukin 1b (a) or the endoplasmic reticulum stressor tunicamycin (b) determined by qPCR and normalised to GAPDH. Data from 3 independent experiments are shown. ^∗ P < 0.05.

Figure 3

Correlation of hepatic GDF15 expression with steatosis and inflammation. (a, b) Hepatic GDF15 mRNA expressions correlated with histologically quantified steatosis (a) and IL-1β expression (b). Respective R values and level of significance are shown in each panel. Each dot represents individual patient before or after LAGB.