Acute exogenous acyl-GIP treatment enhances lipid handling and fatty acid oxidation by involving brown fat

  • EMBO Rep. 2025 Nov;26(21):5154-5171. doi: 10.1038/s44319-025-00582-7.
Sulayman A Lyons  #  1 ,  Micah B S Lea  #  1 ,  Mihir Parikh  1 ,  Zhengzhang Guo  1 ,  Samrin Kagdi  1 ,  Abigail R Bisnauth  1 ,  Jonathan R Pitino  1 ,  Sabrina Ziai  1 ,  Negar Mir  1 ,  Aidan D Tyrrell  1 ,  Yan Fu  1 ,  Chuck T Chen  1 ,  Adam H Metherel  1 ,  Richard P Bazinet  1 ,  Bin Yang  2  3 ,  Patrick J Knerr  2  4 ,  Jonathan D Douros  2  4 ,  Jonathan E Campbell  5 ,  Jacqueline L Beaudry  6
Affiliations
  • 1. Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
  • 2. Novo Nordisk Research Center, Indianapolis, IN, USA.
  • 3. Dexatide LLC, Plainfield, IN, USA.
  • 4. Indiana Biosciences Research Institute, Indianapolis, IN, USA.
  • 5. Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
  • 6. Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. [email protected].
  • # Contributed equally.
PMID: 40983752 DOI: 10.1038/s44319-025-00582-7
Abstract

The contribution of glucose-dependent insulinotropic polypeptide receptor (GIPR) signalling in brown adipose tissue (BAT) remains underexplored. We studied the acute effects of exogenous acyl-GIP (1 nmol/kg) administration on whole-body lipid handling and fatty acid oxidation, using lipid tolerance tests (LTT) and indirect calorimetry, respectively. We demonstrate that in obese male mice, acute acyl-GIP administration improves lipid tolerance; however, pharmacological inhibition of GIPR, or genetic removal of GIPR globally or with the Myf5-Cre driver, completely abolishes GIP-mediated improvements in lipid tolerance, implicating GIPR in BAT. GIP-mediated improvements in lipid tolerance are associated with an increase in BAT lipid uptake, linked to increases in BAT lipoprotein Lipase activity. Our data also reveal that BAT GIPR signalling is necessary for GIP-mediated increases in whole-body fatty acid oxidation, as Myf5-Cre: Gipr mice do not shift substrate oxidation upon GIP administration. Our findings suggest that BAT should be more closely considered in studies examining GIP's effects on whole-body metabolism in rodent models.

Keywords
Brown Adipose Tissue; Glucose-dependent Insulinotropic Polypeptide; Lipid Metabolism.
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