Journal of the Endocrine Society · 2024
Sexual Dimorphism in the Immunometabolic Role of Gpr183 in Mice.
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von Voss Liv, Arora Tulika, Assis Juliana, Kuentzel Katharina B, Arfelt Kristine N, Nøhr Mark K, Grevengoed Trisha J, Arumugam Manimozhiyan, Mandrup-Poulsen Thomas, Rosenkilde Mette M
Аннотация
CONTEXT: Excessive eating and intake of a Western diet negatively affect the intestinal immune system, resulting in compromised glucose homeostasis and lower gut bacterial diversity. The G protein-coupled receptor GPR183 regulates immune cell migration and intestinal immune response and has been associated with tuberculosis, type 1 diabetes, and inflammatory bowel diseases.
OBJECTIVE: We hypothesized that with these implications, GPR183 has an important immunometabolic role and investigated this using a global Gpr183 knockout mouse model.
METHODS: Wild-type (WT) and Gpr183-deficient (Gpr183-/-) mice were fed a high-fat, high-sucrose diet (HFSD) for 15 weeks. We investigated changes in weight, body composition, fecal immunoglobulin A (IgA) levels, fecal microbiome, and glucose tolerance before and after the diet. Macrophage infiltration into visceral fat was determined by flow cytometry, and hepatic gene expression was measured.
RESULTS: A sexual dimorphism was discovered, whereby female Gpr183-/- mice showed adverse metabolic outcomes compared to WT counterparts with inferior glucose tolerance, lower fecal IgA levels, and increased macrophage infiltration in visceral fat. In contrast, male Gpr183-/- mice had significantly lower fasting blood glucose after diet than male WT mice. Liver gene expression showed reduced inflammation and macrophage markers in Gpr183-/- livers, regardless of sex, while the pancreatic islet area did not differ between the groups. No conclusive differences were found after microbiome sequencing.
CONCLUSION: Gpr183 maintains metabolic homeostasis in female but not in male mice independent of diet. If confirmed in humans, future therapy targeting GPR183 should consider this sexual dimorphism.
OBJECTIVE: We hypothesized that with these implications, GPR183 has an important immunometabolic role and investigated this using a global Gpr183 knockout mouse model.
METHODS: Wild-type (WT) and Gpr183-deficient (Gpr183-/-) mice were fed a high-fat, high-sucrose diet (HFSD) for 15 weeks. We investigated changes in weight, body composition, fecal immunoglobulin A (IgA) levels, fecal microbiome, and glucose tolerance before and after the diet. Macrophage infiltration into visceral fat was determined by flow cytometry, and hepatic gene expression was measured.
RESULTS: A sexual dimorphism was discovered, whereby female Gpr183-/- mice showed adverse metabolic outcomes compared to WT counterparts with inferior glucose tolerance, lower fecal IgA levels, and increased macrophage infiltration in visceral fat. In contrast, male Gpr183-/- mice had significantly lower fasting blood glucose after diet than male WT mice. Liver gene expression showed reduced inflammation and macrophage markers in Gpr183-/- livers, regardless of sex, while the pancreatic islet area did not differ between the groups. No conclusive differences were found after microbiome sequencing.
CONCLUSION: Gpr183 maintains metabolic homeostasis in female but not in male mice independent of diet. If confirmed in humans, future therapy targeting GPR183 should consider this sexual dimorphism.