LSG and RYGB-induced upregulation of apoA-IV is beneficial for insulin secretion and energy expenditure

Chinese and Singaporean researchers have discovered that apolipoprotein A-IV (apoA-IV) was significantly increased in diabetic patients living with obesity after laparoscopic sleeve gastrectomy (LSG), and similar changes were observed in patients after Roux-en-Y gastric bypass (RYGB). Furthermore, apoA-IV and its derivative peptide, T55−121, improved energy expenditure and glucose tolerance in diabetic mice.

It has been known that apoA-IV is synthesised primarily by enterocytes in the small intestine and dietary lipids stimulate its production. Several studies have shown that apoA-IV regulates blood glucose levels. However, whether and how apoA-IV enhances insulin secretion in humans is still unknown. The research provides strong evidence of the relationship between apoA-IV and glycaemic control.

The researchers first performed proteomic analysis of sera from patients before and after LSG or RYGB surgery. The data consistently showed a significant increase in apoA-IV levels and long-term improvement in glycaemic control. Subsequently, the potential role of apoA-IV in improving glucose homeostasis was further explored through direct administration of exogenous apoA-IV and in vivo overexpression of apoA-IV using adeno-associated viruses (AAVs). All the results showed that apoA-IV could improve glucose tolerance in both wild-type and diabetic mice.

Next, the researchers investigated whether apoA-IV is involved in insulin secretion and the potential mechanism. The results showed that apoA-IV acted on pancreatic β-cells partly through the Gαs-coupled GPCR/cAMP (G protein-coupled receptor-cyclic adenosine monophosphate) pathway, thereby promoting insulin secretion.

Since glucose metabolism plays a crucial role in energy homeostasis, the study sought to determine whether apoA-IV affects energy homeostasis in the body. Through indirect calorimetry, a significant increase in oxygen consumption (VO2), carbon dioxide production (VCO2), and heat expenditure (HE), as well as a significant increase in metabolic rate, was found in apoA-IV-treated mice, suggesting that apoA-IV enhanced energy expenditure.

Finally, the researchers used Gaussian network modelling to predict apoA-IV functional peptides, indicating that the truncated peptide 55−121 (T55−121) could be a potential functional peptide of apoA-IV in mice. After a glucose tolerance test, T55−121 improved glucose tolerance, promoted insulin secretion from MIN6 cells, and increased oxygen consumption, which was consistent with full-length apoA-IV's enhanced energy expenditure.

The researchers said that these data provide new therapeutic ideas and strategies for improving glucose homeostasis.

The findings were reported in the paper, ‘Apolipoprotein A-IV and its derived peptide, T55−121, improve glycaemic control and increase energy expenditure’, published in Life Metabolism.