Beneficial metabolic effects of PAHSAs depend on the gut microbiota in diet-induced obese mice but not in chow-fed mice

Jennifer Lee, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215.
Kerry Wellenstein, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215.
Ali Rahnavard, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, George Washington University, Washington, DC 20052.
Andrew T. Nelson, Division of Pharmaceutical Chemistry, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093.
Marlena M. Holter, Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Cornell University, Ithaca, NY 14850.
Bethany P. Cummings, Department of Surgery, School of Medicine, University of California, Davis, Sacramento, CA 95817.
Vladimir Yeliseyev, Massachusetts Host-Microbiome Center, Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115.
Angela Castoldi, Laboratory of Immunopathology Keizo Asami, Federal University of Pernambuco, Recife 50670-901, Brazil.
Clary B. Clish, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142.
Lynn Bry, Massachusetts Host-Microbiome Center, Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115.
Dionicio Siegel, Division of Pharmaceutical Chemistry, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093.
Barbara B. Kahn, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215.

Document Type

Journal Article

Publication Date

7-9-2024

Journal

Proceedings of the National Academy of Sciences of the United States of America

Volume

121

Issue

28

DOI

10.1073/pnas.2318691121

Keywords

Bacteroides thetaiotaomicron; PAHSAs; diet-induced obesity; glucose metabolism; gut microbiota

Abstract

Dietary lipids play an essential role in regulating the function of the gut microbiota and gastrointestinal tract, and these luminal interactions contribute to mediating host metabolism. Palmitic Acid Hydroxy Stearic Acids (PAHSAs) are a family of lipids with antidiabetic and anti-inflammatory properties, but whether the gut microbiota contributes to their beneficial effects on host metabolism is unknown. Here, we report that treating chow-fed female and male germ-free (GF) mice with PAHSAs improves glucose tolerance, but these effects are lost upon high fat diet (HFD) feeding. However, transfer of feces from PAHSA-treated, but not vehicle-treated, chow-fed conventional mice increases insulin sensitivity in HFD-fed GF mice. Thus, the gut microbiota is necessary for, and can transmit, the insulin-sensitizing effects of PAHSAs in HFD-fed GF male mice. Analyses of the cecal metagenome and lipidome of PAHSA-treated mice identified multiple lipid species that associate with the gut commensal () and with insulin sensitivity resulting from PAHSA treatment. Supplementing live, and to some degree, heat-killed to HFD-fed female mice prevented weight gain, reduced adiposity, improved glucose tolerance, fortified the colonic mucus barrier and reduced systemic inflammation compared to HFD-fed controls. These effects were not observed in HFD-fed male mice. Furthermore, ovariectomy partially reversed the beneficial effects on host metabolism, indicating a role for sex hormones in mediating the probiotic effects. Altogether, these studies highlight the fact that PAHSAs can modulate the gut microbiota and that the microbiota is necessary for the beneficial metabolic effects of PAHSAs in HFD-fed mice.

Department

Biostatistics and Bioinformatics

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