CTRP12 ablation differentially affects energy expenditure, body weight, and insulin sensitivity in male and female mice

Abstract

Secreted hormones facilitate tissue crosstalk to maintain energy balance. We have previously described C1q/TNF-related protein 12 (CTRP12) as a novel metabolic hormone. Gain-of-function and partial deficiency mouse models have highlighted important roles for this fat-derived adipokine in modulating systemic metabolism. Whether CTRP12 is essential and required for metabolic homeostasis is unknown. We show here that homozygous deletion of Ctrp12 gene results in sexually dimorphic phenotypes. Under basal conditions, complete loss of CTRP12 has little impact on male mice, whereas it decreased body weight (driven by reduced lean mass and liver weight) and improved insulin sensitivity in female mice. When challenged with a high-fat diet, Ctrp12 knockout (KO) male mice have decreased energy expenditure, increased weight gain and adiposity, elevated serum TNF-α level, and reduced insulin sensitivity. In contrast, female KO mice have reduced weight gain and liver weight. The expression of lipid synthesis and catabolism genes, as well as pro-fibrotic, endoplasmic reticulum (ER) stress, and oxidative stress genes are largely unaffected in the adipose tissue of Ctrp12-KO male mice. Despite greater adiposity and insulin resistance, Ctrp12-KO male mice fed an obesogenic diet have lower circulating triglyceride and free fatty acid levels. In contrast, lipid profiles of the leaner female KO mice are not different from WT controls. These data suggest that CTRP12 contributes to whole-body energy metabolism in genotype-, diet-, and sex-dependent manners, underscoring complex gene-environment interactions influencing metabolic outcomes.