Mol Metab. 2025 Jun 10:98:102184. doi: 10.1016/j.molmet.2025.102184

Deletion of PPARα in mouse brown adipocytes increases their De Novo Lipogenesis

Pierre-Louis Batrow¹, Sylvie Caspar-Bauguil², Nathalie Rochet¹, Nadine Gautier¹, Anne-Sophie Rousseau¹, Marielle Maret³, Samah Rekima¹, Etienne Mouisel⁴, Emmanuel Van Obberghen⁵, Christian H Roux⁶, Hervé Guillou⁷, Catherine Postic⁸, Christian Wolfrum⁹, Dominique Langin¹⁰, Ez-Zoubir Amri¹, Isabelle Mothe-Satney¹¹

Affiliations
¹Université Côte d’Azur, CNRS, Inserm, Adipocible Research Study Group, Institut de Biologie Valrose (iBV), Nice, France.
²Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III University – Paul Sabatier (UPS), Toulouse, France; Department of Medical Biochemistry, Toulouse University Hospitals, France.
³Université Côte d’Azur, CNRS, Inserm, IRCAN, Nice, France.
⁴Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III University – Paul Sabatier (UPS), Toulouse, France.
⁵Université Côte d’Azur, CNRS, Laboratoire de PhysioMédecine Moléculaire (LP2M), Laboratories of Excellence Ion Channel Science and Therapeutics, Nice, France.
⁶Université Côte d’Azur, CNRS, Inserm, Adipocible Research Study Group, Institut de Biologie Valrose (iBV), Nice, France; Rheumatology Department, Hospital Pasteur 2 CHU, Adipocible Research Study Group, 06000, Nice, France.
⁷Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France.
⁸Université Paris Cité, Institut Cochin, CNRS, Inserm, Paris, France.
⁹Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.
¹⁰Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III University – Paul Sabatier (UPS), Toulouse, France; Department of Medical Biochemistry, Toulouse University Hospitals, France; Institut Universitaire de France (IUF), Paris, France.
¹¹Université Côte d’Azur, CNRS, Inserm, Adipocible Research Study Group, Institut de Biologie Valrose (iBV), Nice, France.

Abstract

Objective: Peroxisome Proliferator-Activated Receptors (PPARs) are nuclear receptors involved in the control of lipid metabolism. The PPARα isoform is highly expressed in brown adipose tissue (BAT). However, its precise role in BAT remains unclear. Here, we aimed to investigate the role of PPARα in BAT of high fat diet-induced obese mice in a thermoneutral environment.

Methods: We used tamoxifen-inducible-BAT specific PPARα knockout mice (PPARαBATKO) that were housed at thermoneutrality to minimize BAT basal activation, fed a high-fat diet for 20 weeks and challenged with a β3-adrenergic agonist (CL316,243) during the last week. Both male and female mice were studied.

Results: Body weight and glucose tolerance tests were similar in both sexes and genotypes. However, BAT morphology was altered in PPARαBATKO mice, with more unilocular and larger lipid droplets compared to control mice, suggesting BAT impaired function. Indeed, when treated with CL316,243, both male and female mice had increased De Novo Lipogenesis (DNL), reflected by an increased expression of ChREBPβ and lipogenic enzymes ACLY, ACC1, FASN and SCD1. These changes were accompanied by an increase in fatty acids in triglycerides, and thus an increase in lipid storage. Moreover, lipid profiles in phospholipids were different, suggesting a modification in the membrane content with an increase of palmitoleate.

Conclusions: Altogether, our results reveal a key role for PPARα in DNL in BAT and in the regulation of lipid metabolism in HFD-induced obesity.

DOI: 10.1016/j.molmet.2025.102184