New Insight into the Mechanisms of Ectopic Fat Deposition Improvement after Bariatric Surgery

Abstract

non-alcoholic fatty-liver disease (nAfLD) is frequent in obese patients and represents a major risk factor for the development of diabetes and its complications. Bariatric surgery reverses the hepatic features of nAfLD. However, its mechanism of action remains elusive. We performed a comprehensive analysis of the mechanism leading to the improvement of nAfLD and insulin resistance in both obese rodents and humans following sleeve-gastrectomy (SG). SG improved insulin sensitivity and reduced hepatic and monocyte fat accumulation. importantly, fat accumulation in monocytes was well comparable to that in hepatocytes, suggesting that Plin2 levels in monocytes might be a noninvasive marker for the diagnosis of nAfLD. Both in vitro and in vivo studies demonstrated an effective metabolic regeneration of liver function and insulin sensitivity. Specifically, SG improved NAFLD significantly by enhancing AMP-activated protein kinase (AMPK) phosphorylation and chaperonemediated autophagy (CMA) that translate into the removal of Plin2 coating lipid droplets. This led to an increase in lipolysis and specific amelioration of hepatic insulin resistance. Elucidating the mechanism of impaired liver metabolism in obese subjects will help to design new strategies for the prevention and treatment of nAfLD. Non-alcoholic fatty liver disease (NAFLD) affects about 25% of the general population with peaks of 32% in Middle East and 30% in South America 1. A recent study demonstrated a linear relationship between body mass index (BMI) and NAFLD diagnosis, which was about 5-to 9-fold higher in subjects with a BMI between 30 and 32.5 kg/m 2 increasing to ca. 10-to 14-fold at BMIs of 37.5-40 kg/m 2 as compared with normal weight subjects 2. The prevalence of NAFLD in type 2 diabetes (T2D) is estimated to be around 60% 3. Non-alcoholic steatohepatitis (NASH) is a more aggressive form of NAFLD characterized by the presence of inflammatory cell infiltration and hepatocyte ballooning, which may further progress to cirrhosis and/or to hepatocellular carcinoma 1. Currently, there are no drugs approved to specifically treat NAFLD or NASH and thus weight loss remains the only approach. Bariatric surgery (BS) promotes T2D remission both in the short and in the long term 4-10 , as well as remission of both NAFLD and NASH 11. The major effect of SG is to reduce energy intake. It is known that a reduced energy intake activates AMP-activated protein kinase (AMPK) in its phosphorylated form that tends to counterbalance a low energy status and restores energy balance through the inhibition of ATP consumption and simultaneous promotion of

Nonalcoholic fatty liver disease or metabolic dysfunction‐associated fatty liver disease diagnoses and cardiovascular diseases: From epidemiology to drug approaches

“…The accumulation of ectopic fat can thus be a marker of NAFLD and, while in humans it is best represented by EFT, in rodents it may be characterized by hepatocyte accumulation of neutral lipids forming lipid droplets (LDs) surrounded by proteins of which perilipin2 (PLIN2) is a major component 154 . PLIN2 appears to be a potentially protective factor against NAFLD, 155 since reduction of PLIN2 in monocytes occurs after bariatric surgery 156 . As a general consequence, obese patients with NAFLD treated with bariatric surgery show improved insulin sensitivity and reduced liver and monocyte fat accumulation 6 …”