Exogenous GLP-1 stimulates TCA cycle and suppresses gluconeogenesis and ketogenesis in late-fasted northern elephant seals pups

Authors: DHILLON, JAAPNA - University Of California; VISCARRA, JOSE - University Of California; Newman, John; FIEHN, OLIVER - University Of California, Davis; CROCKER, DANIEL - Sonoma State University; ORTIZ, RUDY - University Of California

Submitted to: American Journal of Physiology - Regulatory Integrative & Comparative Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/5/2021
Publication Date: 4/1/2021
Citation: Dhillon, J., Viscarra, J.A., Newman, J.W., Fiehn, O., Crocker, D.E., Ortiz, R.M. 2021. Exogenous GLP-1 stimulates TCA cycle and suppresses gluconeogenesis and ketogenesis in late-fasted northern elephant seals pups. American Journal of Physiology - Regulatory Integrative & Comparative Physiology. 320(4):R393-R401. https://doi.org/10.1152/ajpregu.00211.2020.
DOI: https://doi.org/10.1152/ajpregu.00211.2020

Interpretive Summary: The post-weaning fast of northern elephant seal pups provides and extreme model of adaptive physiology in mammalian energy metabolism. During the post-weaning fast, energy metabolism is lipid-dependent, and is associated with a decrease in plasma glucose and glucose-metabolism stimulating hormones including glucagon-like peptide-1 (GLP-1) and insulin, and an increase in gluconeogeneisis (i.e. the biosynthesis of glucose from molecular precursors) and ketogenesis (i.e. the production of ketone bodies from fatty acids) to supply energy to critical tissues. We have previously demonstrated that exogenous GLP-1 infusion increased plasma insulin despite simultaneous increases in cortisol and glucagon, which collectively present contradictory regulatory stimuli of gluconeogenesis (GNG), ketogenesis, and glycolysis (i.e. the breakdown of glucose to produce energy). To better understand the metabolic impacts of these contradictory findings, we used a metabolomics approach exploring changes in an array of small molecules in plasma to investigate the impact of GLP-1 infusions on energy metabolism. Specifically, late-fasted seal pups were with either low (LDG; 10 pM/kg; n=3) or high (HDG; 100 pM/kg; n=4) levels of GLP-1 immediately following a glucose bolus (0.5g/kg). Glucose without GLP-1 was used as the control (n=5). Infusions were performed in similarly aged animals 6-8 weeks into their post-weaning fast. The plasma metabolome was measured from samples collected at 5 time points just prior to and during the infusions, and network maps were constructed to robustly evaluate the effects of GLP-1 on primary carbon metabolism. HDG increased tricarboxylic acid cycle metabolites, and decreased phosphoenolpyruvate and acetoacetate suggesting that elevated levels of GLP-1 promoted glycolysis and suppressed GNG and ketogenesis, which collectively increase glucose clearance. These GLP1-mediated effects on cellular metabolism help to explain why plasma GLP 1 concentrations decrease naturally in fasting pups as an evolved mechanism to help conserve glucose, the preferred energy source for the brain, during the late-fasting period.

Technical Abstract: The post-weaning fast of northern elephant seal pups is characterized by a lipid-dependent metabolism, and associated with a decrease in plasma glucagon-like peptide-1 (GLP-1), insulin, and glucose and increased gluconeogenesis and ketogenesis. We have also demonstrated that exogenous GLP-1 infusion increased plasma insulin despite simultaneous increases in cortisol and glucagon, which collectively present contradictory regulatory stimuli of gluconeogenesis (GNG), ketogenesis, and glycolysis. To assess the effects of GLP-1 on metabolism using primary carbon metabolite profiles in late-fasted seal pups, we dose-dependently infused late-fasted seals with low (LDG; 10 pM/kg; n=3) or high (HDG; 100 pM/kg; n=4) GLP-1 immediately following a glucose bolus (0.5g/kg), using glucose without GLP-1 as control (n=5). Infusions were performed in similarly aged animals 6-8 weeks into their post-weaning fast. The plasma metabolome was measured from samples collected at 5 time points just prior to and during the infusions, and network maps constructed to robustly evaluate the effects of GLP-1 on primary carbon metabolism. HDG increased TCA cycle metabolites, and decreased phosphoenolpyruvate and acetoacetate suggesting that elevated levels of GLP-1 promote glycolysis and suppress GNG and ketogenesis, which collectively increase glucose clearance. These GLP1-mediated effects on cellular metabolism help to explain why plasma GLP-1 concentrations decrease naturally in fasting pups as an evolved mechanism to help conserve glucose during the late-fasting period.