AdipoRon exerts opposing effects on insulin sensitivity via fibroblast growth factor 21-mediated time-dependent mechanisms.

Increasing evidence has shown that AdipoRon, a synthetic adiponectin receptor agonist, is involved in the regulation of whole-body insulin sensitivity and energy homeostasis. However, the mechanisms underlying these alterations remain unclear. Here, using hyperinsulinemic-euglycemic clamp and isotopic tracing techniques, we show that short-term (10 days) AdipoRon administration indirectly inhibits lipolysis in white adipose tissue via increasing circulating levels of fibroblast growth factor 21 in mice fed a high-fat diet. This led to reduced plasma-free fatty acid concentrations and improved lipid-induced whole-body insulin resistance. In contrast, we found that long-term (20 days) AdipoRon administration directly exacerbated white adipose tissue lipolysis, increased hepatic gluconeogenesis, and impaired the tricarboxylic acid cycle in the skeletal muscle, resulting in aggravated whole-body insulin resistance. Together, these data provide new insights into the comprehensive understanding of multifaceted functional complexity of AdipoRon.

2,3,5,6-Tetramethylpyrazine improves diet-induced whole-body insulin resistance via suppressing white adipose tissue lipolysis in mice.

Ectopic lipid accumulation in skeletal muscle and liver arises when nutrient storage systems are exposed to chronic energy surplus, leading to whole-body insulin resistance and metabolic disorders. One recent study has shown 2,3,5,6-tetramethylpyrazine (TMP), highly enriched in roasted foodstuffs, such as cocoa and peanuts, significantly decreases blood lipids levels and ameliorates ApoE-defect induced atherosclerosis suggesting a potent role of TMP in lipid dysregulation improvement. Here, we evaluated the impact of TMP treatment on high fat diet (HFD)-induced insulin resistance. Using hyperinsulinemic-euglycemic mouse clamp, we demonstrated 4-week TMP treatment improved whole-body insulin resistance in HFD-fed mice through suppressing lipolysis in white adipose tissue associated with reduced triglyceride in liver and improved glucose uptake in skeletal muscle. Collectively, our work provides proof-of-concept data to support the development of white adipose tissue-targeted medicine for the treatment of metabolic disorder.

Protocatechuic Acid Ameliorates High Fat Diet-Induced Obesity and Insulin Resistance in Mice.

SCOPE: Insulin resistance is a common feature of obesity and type 2 diabetes and partly results from an imbalance between food intake and energy expenditure. Therefore, efficient and safe insulin resistance treatment therapies are warranted. This work is aim to access the impact of protocatechuic acid (PCA), a catechol-type O-diphenol phenolic acid, in high fat diet (HFD)-induced glucose, and lipid dysregulation. METHODS AND RESULTS: Five-week-old male C57BL/6 mice are fed with HFD for 4 weeks and then are randomly divided into two cohorts: one cohort feed with HFD is free access to sterile water for 4 weeks, another cohort is free access to PCA-containing water (2.7 mM) for 4 weeks with HFD. In this study, using a hyperinsulinemic-euglycemic mouse clamp, it is showed that PCA-treated mice display improved systemic insulin resistance via enhanced fatty acid mobilization and utilization, thereby reducing ectopic lipid accumulation and promoting hepatic and peripheral insulin action. CONCLUSIONS: This study provides insights on the potent pharmacological effects of PCA from food sources on improving high fat diet (HFD)-induced whole-body insulin resistance and type 2 diabetes.