(P30-007-23) Macrophage-Specific Histone Deacetylase 9 Deletion Exacerbates Obesity-Induced Metabolic Dysfunction in Male Mice

Objectives: We investigated the role of macrophage histone deacetylase 9 (Hdac9) on the pathogenesis of obesity-associated metabolic dysfunctions and inflammation using macrophage-specific Hdac9 knockout mice (Hdac9^MKO).

Methods: Hdac9^MKO mice were generated by breeding homozygous Hdac9^fl/fl mice with lysozyme M Cre mice. Male and female Hdac9 wild-type (WT) (n=9-10) and Hdac9^MKO (n=9-12) mice at 8 weeks old were fed a high-fat/high-sucrose/high-cholesterol (HF) diet for 16 weeks. Indirect calorimetry, EchoMRI and oral glucose tolerance tests were conducted at weeks 10-12. After 16 weeks on the HF diet, serum and tissue samples were collected from mice for analysis.

Results: Serum total cholesterol and glucose levels were higher in male Hdac9MKO mice, whereas triglycerides were lower in female Hdac9^MKO mice than in WT mice. Hdac9^MKO mice showed increased body weight, fat mass, inguinal white adipose tissue weight, gonadal white adipose tissue (gWAT) weight, and gWAT crown-like structure number in males but not females. Although liver weight was significantly increased in male Hdac9^MKO mice, the hepatic expression of macrophage markers and inflammatory genes was not significantly different between male genotypes. However, female Hdac9^MKO had higher hepatic expression of inflammatory genes with decreased M2 macrophage markers than WT, despite no significant difference in liver weight between genotypes. Finally, male but not female Hdac9^MKO mice exhibited lower metabolic rates (VO₂ and VCO₂) and energy expenditure than WT, with no changes in respiratory exchange ratio and physical activity between genotypes.

Conclusions: Hdac9 deletion in macrophages increased body and WAT weights, fat mass, and inflammation, which is attributed, at least partly, to decreased metabolic rates and energy expenditure in male obese mice. The changes were not observed in female mice, suggesting a crucial impact of macrophage Hdac9 on whole-body energy metabolism in a sex-dependent manner.

Funding Sources: Supported by the funds from the College of Agriculture, Health and Natural Resources at the University of Connecticut