Non-alcoholic fatty liver disease (NAFLD) is a multifaceted metabolic disorder, whose spectrum covers clinical, histological and pathophysiological developments ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and liver fibrosis, potentially evolving into cirrhosis, hepatocellular carcinoma and liver failure. Liver biopsy remains the gold standard for diagnosing NAFLD, while there are no specific treatments. An ever-increasing number of high-throughput Omics investigations on the molecular pathobiology of NAFLD at the cellular, tissue and system levels produce comprehensive biochemical patient snapshots. In the clinical setting, these applications are considerably enhancing our efforts towards obtaining a holistic insight on NAFLD pathophysiology. Omics are also generating non-invasive diagnostic modalities for the distinct stages of NAFLD, that remain though to be validated in multiple, large, heterogenous and independent cohorts, both cross-sectionally as well as prospectively. Finally, they aid in developing novel therapies. By tracing the flow of information from genomics to epigenomics, transcriptomics, proteomics, metabolomics, lipidomics and glycomics, the chief contributions of these techniques in understanding, diagnosing and treating NAFLD are summarized herein.

Based on studies in mice, leptin was expected to decrease body weight in obese individuals. However, the majority of the obese are hyperleptinemic and do not respond to leptin treatment, suggesting the presence of leptin tolerance and questioning the role of leptin as regulator of energy balance in humans. We thus performed detailed novel measurements and analyses of samples and data from our clinical trials biobank to investigate leptin effects on mechanisms of weight regulation in lean normo- and mildly hypo-leptinemic individuals without genetic disorders. We demonstrate that short-term leptin administration alters food intake during refeeding after fasting, whereas long-term leptin treatment reduces fat mass and body weight, and transiently alters circulating free fatty acids in lean mildly hypoleptinemic individuals. Leptin levels before treatment initiation and leptin dose do not predict the observed weight loss in lean individuals suggesting a saturable effect of leptin. In contrast to data from animal studies, leptin treatment does not affect energy expenditure, lipid utilization, SNS activity, heart rate, blood pressure or lean body mass.

CHS‐131 is a selective peroxisome proliferator‐activated receptor gamma modulator with antidiabetic effects and less fluid retention and weight gain compared to thiazolidinediones in phase II clinical trials. We investigated the effects of CHS‐131 on metabolic parameters and liver histopathology in a diet‐induced obese (DIO) and biopsy‐confirmed mouse model of nonalcoholic steatohepatitis (NASH). Male C57BL/6JRj mice were fed the amylin liver NASH diet (40% fat with trans‐fat, 20% fructose, and 2% cholesterol). After 36 weeks, only animals with biopsy‐confirmed steatosis and fibrosis were included and stratified into treatment groups (n = 12‐13) to receive for the next 12 weeks (1) low‐dose CHS‐131 (10 mg/kg), (2) high‐dose CHS‐131 (30 mg/kg), or (3) vehicle. Metabolic parameters, liver pathology, metabolomics/lipidomics, markers of liver function and liver, and subcutaneous and visceral adipose tissue gene expression profiles were assessed. CHS‐131 did not affect body weight, fat mass, lean mass, water mass, or food intake in DIO‐NASH mice with fibrosis. CHS‐131 improved fasting insulin levels and insulin sensitivity as assessed by the intraperitoneal insulin tolerance test. CHS‐131 improved total plasma cholesterol, triglycerides, alanine aminotransferase, and aspartate aminotransferase and increased plasma adiponectin levels. CHS‐131 (high dose) improved liver histology and markers of hepatic fibrosis. DIO‐NASH mice treated with CHS‐131 demonstrated a hepatic shift to diacylglycerols and triacylglycerols with a lower number of carbons, increased expression of genes stimulating fatty acid oxidation and browning, and decreased expression of genes promoting fatty acid synthesis, triglyceride synthesis, and inflammation in adipose tissue. Conclusion: CHS‐131 improves liver histology in a DIO and biopsy‐confirmed mouse model of NASH by altering the hepatic lipidome, reducing insulin resistance, and improving lipid metabolism and inflammation in adipose tissue.

Aim To examine how circulating glucagon‐like peptide‐1 (GLP‐1) concentrations during liraglutide treatment relate to its therapeutic actions on glucose and weight, and to study the effects of liraglutide on other proglucagon‐derived peptides (PGDPs), including endogenous GLP‐1, glucagon‐like peptide‐2, glucagon, oxyntomodulin, glicentin and major proglucagon fragment, which also regulate metabolic and weight control. Materials and Methods Adults who were overweight/obese (body mass index 27‐40 kg/m2) with prediabetes were randomized to liraglutide (1.8 mg/day) versus placebo for 14 weeks. We used specific assays to measure exogenous (liraglutide, GLP‐1 agonist [GLP‐1A]) and endogenous (GLP‐1E) GLP‐1, alongside five other PGDP concentrations during a mixed meal tolerance test (MMTT) completed at baseline and at week 14 (liraglutide, n = 16; placebo, n = 19). Glucose during MMTT, steady‐state plasma glucose (SSPG) concentration for insulin resistance and insulin secretion rate (ISR) were previously measured. MMTT area‐under‐the‐curve (AUC) was calculated for ISR, glucose and levels of PGDPs. Results Participants on liraglutide versus placebo had significantly (P ≤ .004) decreased weight (mean −3.6%, 95% CI [−5.2% to −2.1%]), SSPG (−32% [−43% to −22%]) and glucose AUC (−7.0% [−11.5% to −2.5%]) and increased ISR AUC (30% [16% to 44%]). GLP‐1A AUC at study end was significantly (P ≤ .04) linearly associated with % decrease in weight (r = −0.54) and SSPG (r = −0.59) and increase in ISR AUC (r = 0.51) in the liraglutide group. Treatment with liraglutide significantly (P ≤ .005) increased exogenous GLP‐1A AUC (median 310 vs. 262 pg/mL × 8 hours at baseline but decreased endogenous GLP‐1E AUC [13.1 vs. 24.2 pmol/L × 8 hours at baseline]), as well as the five other PGDPs. Decreases in the PGDPs processed in the intestines are independent of weight loss, indicating a probable direct effect of GLP‐1 receptor agonists to decrease their endogenous production in contrast to weight loss‐dependent changes in glucagon and major proglucagon fragment that are processed in pancreatic alpha cells. Conclusions Circulating GLP‐1A concentrations, reflecting liraglutide levels, predict improvement in weight, insulin action and secretion in a linear manner. Importantly, liraglutide also downregulates other PGDPs, normalization of the levels of which may provide additional metabolic and weight loss benefits in the future.