Summary Non-alcoholic fatty liver disease (NAFLD) affects one in three Americans and is a major predisposing condition for type 2 diabetes (T2D), however there are currently no drugs available to treat this disease. We examined whether a functionally liver-targeted derivative of 2,4-dinitrophenol (DNP), DNP-methyl ether (DNPME), could safely decrease hypertriglyceridemia, NAFLD and insulin resistance without systemic toxicities. Treatment with DNPME reversed hypertriglyceridemia, fatty liver and whole-body insulin resistance in high-fat fed rats and decreased hyperglycemia in a rat model of T2D with a wide therapeutic index. The reversal of liver and muscle insulin resistance was associated with reductions in tissue diacylglycerol content and reductions in PKCε and PKCθ activity in liver and muscle respectively. These results demonstrate that the beneficial effects of DNP on hypertriglyceridemia, fatty liver and insulin resistance can be dissociated from systemic toxicities and suggest the potential utility of liver-targeted mitochondrial uncoupling agents for the treatment of the related epidemics of NAFLD, metabolic syndrome and type 2 diabetes.

Non-alcoholic fatty liver disease (NAFLD) and insulin resistance have recently been found to be associated with increased plasma concentrations of apolipoprotein CIII (APOC3) in humans carrying single nucleotide polymorphisms within the insulin response element of the APOC3 gene. To examine whether increased expression of APOC3 would predispose mice to NAFLD and hepatic insulin resistance, human APOC3 overexpressing (ApoC3Tg) mice were metabolically phenotyped following either a regular chow or high-fat diet (HFD). After HFD feeding, ApoC3Tg mice had increased hepatic triglyceride accumulation, which was associated with cellular ballooning and inflammatory changes. ApoC3Tg mice also manifested severe hepatic insulin resistance assessed by a hyperinsulinemic-euglycemic clamp, which could mostly be attributed to increased hepatic diacylglycerol content, PKCε activation and decreased insulin-stimulated Akt2 activity. Increased hepatic triglyceride content in the HFD fed ApoC3Tg mice could be attributed to a ~70% increase in hepatic triglyceride uptake and ~50% reduction hepatic triglyceride secretion. In conclusion these data demonstrate that increase plasma APOC3 concentrations predispose mice to diet-induced NAFLD and hepatic insulin resistance.

No abstract

No abstract

ObjectivesTherapies less invasive than surgery and more effective than lifestyle and pharmacotherapy are needed to contend with the obesity epidemic. Intragastric balloons (IGBs) are a minimally invasive endoscopic weight loss method recently approved for use in the US. The purpose of the study is to assess the effect of IGBs on metabolic outcomes associated with obesity.MethodsMEDLINE, Embase, and Cochrane Database were searched through July 2016. Dual extraction and quality assessment of studies using Cochrane risk of bias tool were performed independently by two authors. Primary outcomes included the change from baseline in metabolic parameters. Secondary outcomes included resolution and/or improvement in metabolic co-morbidities and association with baseline parameters.Results10 randomized controlled trials (RCT) and 30 observational studies including 5,668 subjects were analyzed. There was moderate-quality evidence for improvement in most metabolic parameters in subjects assigned to IGB therapy as compared to conventional non-surgical therapy in RCTs: mean difference (MD) in fasting glucose change: -12.7 mg/dl (95% confidence interval (CI) -21.5, -4); MD in triglycerides: -19 mg/dl (95% CI -42, 3.5); MD in waist circumference: -4.1 cm (95% CI -6.9, -1.4); MD in diastolic blood pressure: -2.9 mm Hg (95% CI -4.1, -1.8). The odds ratio for diabetes resolution after IGB therapy was 1.4 (95% CI 1.3, 1.6). The rate of serious adverse events was 1.3%.ConclusionsIGBs are more effective than diet in improving obesity-related metabolic risk factors with a low rate of adverse effects, however the strength of the evidence is limited given the small number of participants and lack of long-term follow-up.

No abstract

No abstract

The use of intragastric balloon decreases liver enzymes and is potentially an effective short-term treatment for NAFLD as part of a multidisciplinary approach. Larger, more rigorous trials are needed to confirm the effect of IGBs on NAFLD.