Gpr75-Deficient Mice Are Protected From High-Fat Diet-Induced Obesity

Authors

Sakib Hossain, Department of Pharmacology, New York Medical College School of Medicine, Valhalla, New York, USA.
Ankit Gilani, Department of Pharmacology, New York Medical College School of Medicine, Valhalla, New York, USA.
Jonathan Pascale, Department of Pharmacology, New York Medical College School of Medicine, Valhalla, New York, USA.
Elizabeth Villegas, Department of Pharmacology, New York Medical College School of Medicine, Valhalla, New York, USA.
Danielle Diegisser, Department of Pharmacology, New York Medical College School of Medicine, Valhalla, New York, USA.
Kevin Agostinucci, Department of Pharmacology, New York Medical College School of Medicine, Valhalla, New York, USA.Follow
Melissa-Maria Kulaprathazhe, Department of Pharmacology, New York Medical College School of Medicine, Valhalla, New York, USA.
Ercument Dirice, Department of Pharmacology, New York Medical College School of Medicine, Valhalla, New York, USA.
Victor Garcia, Department of Pharmacology, New York Medical College School of Medicine, Valhalla, New York, USA.
Michal Laniado Schwartzman, Department of Pharmacology, New York Medical College School of Medicine, Valhalla, New York, USA.

Author Type(s)

Student, Faculty

Journal Title

Obesity

First Page

1024

Last Page

1037

Document Type

Article

Publication Date

4-1-2023

Department

Pharmacology

Abstract

OBJECTIVE: G-protein coupled receptor 75 (GPR75) has been identified as the high-affinity receptor of 20-hydroxyeicosatetraenoic acid (20-HETE), a vasoactive and proinflammatory lipid, and mice overproducing 20-HETE have been shown to develop insulin resistance when fed a high-fat diet (HFD), which was prevented by a 20-HETE receptor blocker. Simultaneously, a large-scale exome sequencing of 640,000 subjects identified an association between loss-of-function GPR75 variants and protection against obesity. METHODS: Wild-type (WT) and Gpr75-deficient mice were placed on HFD for 14 weeks, and their obesity phenotype was examined. RESULTS: Male and female Gpr75 null (knockout [KO]) and heterozygous mice gained less weight than WT mice when placed on HFD. KO mice maintained the same level of energy expenditure during HFD feeding, whereas WT mice showed a significant reduction in energy expenditure. Diet-driven adiposity and adipocyte hypertrophy were greatly lessened in Gpr75-deficient mice. HFD-fed KO mice did not develop insulin resistance. Adipose tissue from Gpr75-deficient mice had increased expression of thermogenic genes and decreased levels of inflammatory markers. Moreover, insulin signaling, which was impaired in HFD-fed WT mice, was unchanged in KO mice. CONCLUSIONS: These findings suggest that GPR75 is an important player in the control of metabolism and glucose homeostasis and a likely novel therapeutic target to combat obesity-driven metabolic disorders.

Recommended Citation

Hossain, S., Gilani, A., Pascale, J., Villegas, E., Diegisser, D., Agostinucci, K., Kulaprathazhe, M., Dirice, E., Garcia, V., & Schwartzman, M. L. (2023). Gpr75-Deficient Mice Are Protected From High-Fat Diet-Induced Obesity. Obesity, 31 (4), 1024-1037. https://doi.org/10.1002/oby.23692