Chronic supplementation of branched chain amino acids and its impact on glucose and hepatic metabolism during insulin sensitivity

Abstract

Dysfunctional interactions between branched chain amino acids (BCAAs) and facets of glucose and lipid metabolism are central features of insulin resistant tissues. However, it is unclear whether insulin resistance is a prerequisite for the biochemical relationships between BCAAs and macronutrient networks. We hypothesize that BCAAs will enhance glucose and lipid oxidation, lower gluconeogenesis and decrease hepatic de novo lipogenesis to optimize insulin sensitivity. Male mice (C57BL/6NJ) were placed on either a low-fat (LF; 10% fat Kcal) or LF supplemented with 1.5X BCAAs (LB) diet for a period of 12-32 wks. Oxygen consumption and energy expenditure were determined by indirect calorimetry after 12 and 24-wks on the diets. After 32-wks on the diets and a 4-hr fast, LF and LB mice underwent intraperitoneal glucose tolerance test (IPGTT) with the 2g/kg glucose containing 50% [ 13 C 6 ]glucose. Blood glucose was measured every 15-min and blood was collected every 30-min for 2 hours. Enrichment of 13 C from glucose into pyruvate and other metabolic intermediates was determined by gas-chromatography and mass-spectrometry (GC-MS). Following 1-wk of recovery, these LF and LB mice were randomly split into fed and overnight fasted groups. [ 13 C 3 ] pyruvate (20 mg) was injected intraperitoneally to determine the rate of incorporation of pyruvate into glucose via. gluconeogenesis, utilizing GC-MS. Hepatic gene expression in fed and fasted livers were profiled using qPCR. Supplementation of BCAAs for 24-wks increased energy expenditure and oxygen consumption in the LB mice vs. their LF counterparts (p≤0.05). Additionally, IPGTT revealed improved insulin sensitivity in LB mice vs. their LF counterparts (p<0.05). Dilution of [ 13 C 6 ]glucose was lower in the LB plasma by the 90-min time point of the glucose tolerance test (% enrichment; LB; 16.42±0.74 vs. LF; 18.06±0.54, p=0.09), while the LB blood glucose levels during IPGTT remained lower, indicative of higher rates of glucose oxidation in LB mice. Further, following the pyruvate tolerance test, incorporation of [ 13 C 3 ]pyruvate into glucose tended to be higher in the fasted BCAA supplemented group (% enrichment; LB; 11.79±0.23 vs. LF; 10.58±0.53, p=0.07). Basal levels of tricarboxylic acid (TCA) cycle intermediates in plasma were significantly different between LF vs. LB mice (p<0.05). Fed-to-fasted fold induction of genes involved in lipid oxidation ( Lcad, P para) were higher in the LB livers vs. their LF counterparts (p≤0.05). On the contrary, fed-to-fasted suppression of lipogenic gene expression (A cc, F as) was greater in the LB livers vs. their LF counterparts (p<0.05). In summary, our results indicate that chronic BCAA supplementation to insulin sensitive mice positively impacts aspects of glucose and lipid metabolism. The ability of BCAAs to modulate macronutrient metabolism could have beneficial effects in alleviating metabolic dysfunction during early stages of insulin resistance and fatty liver disease. National Institute of Health R01DK112865 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.