Activation of GIP (glucose-dependent insulinotropic peptide) receptor (GIPR) in combination with GLP-1 receptor has demonstrated reduced adiposity and bodyweight in mice. Although the incretin action of GIP in pancreatic beta cells is well characterized, its regulation of adipose tissue metabolism are incompletely understood. Using differentiated human adipocytes we demonstrated GIP suppression of insulin stimulated [14C] glucose and [14C] acetate incorporation into the cellular lipid fraction suggesting GIP/insulin co-regulation of de novo lipogenesis. To further investigate these findings, we employed an NMR and mass spec strategy. Briefly, human adipocytes were differentiated then incubated with [13C] glucose or [13C] acetate overnight in the presence GIP, insulin, GIP + insulin, or control followed by lysate preparation for mass spec and NMR analysis. Isotope label incorporation in lysate fatty acids were determined by HPLC-MS detection of base-hydrolyzed lipids. GIP significantly reduced incorporation of labeled acetate and labeled glucose in fatty acids, both in the presence and absence of insulin. Sample analysis by NMR demonstrated a GIP regulated increase in glycerol production from labeled glucose both in the presence and absence of insulin with little to no acetate incorporation into glycerol under all conditions tested. These findings demonstrate GIP signaling in adipocytes reduces de novo fatty acid synthesis while increasing glycerol formation. This suggests a model whereby GIP suppresses generation of new fatty acids from substrate but enhances appropriate storage capacity of dietary fatty acids by increasing production of glycerol required for triglyceride generation. Further studies will be required to elucidate this potential benefit of GIP to improve nutrient partitioning.
P.L. Milligan: Employee; Self; Eli Lilly and Company. K.D. Roth: Employee; Self; Eli Lilly and Company. H. Hu: None. J. Moyers: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. X. Ruan: Employee; Self; Eli Lilly and Company. W.C. Roell: Employee; Self; Eli Lilly and Company. A. Regmi: Employee; Self; Eli Lilly and Company.