Evaluating the Sex Dependent Influence of Sarcospan on Cardiometabolic Disease Traits in Mice

Numerous genes including sarcospan (SSPN) have been designated as obesity-susceptibility genes by human genome-wide association studies. Variants in the sarcospan (SSPN) gene locus have been associated with obesity traits with a stronger effect in women. To date this association has not been tested in vivo, therefore, we assessed the susceptibility of young (2 month) global SSPN-deficient (SSPN-/-) mice to diet-induced obesity by feeding them high fat diet (HFD) or control diet (CD) for 16 weeks. Anthropometric measurements were used to assess outcomes to the diets including weight change, glucose handling, fat distribution, adipocyte size and effects on cardiac function. To assess the age-dependent impact of SSPN deletion we also compared the response of (13 month) male and female mice to HFD, which were aged by study completion. SSPN deficiency offered modest protection from weight gain in all groups studied, which was not attributable to reduced food consumption. Aging revealed glucose intolerance for SSPN-/- CD mice, which was significant in females. Young female mice had low % Fat and less visceral adipose tissue accumulation that remained relatively unchanged in HFD groups. However, this protection was lost with aging. SSPN-/- mice did not exhibit decrements in cardiac function in response to HFD. However, aged male SSPN-/- CD mice had significantly increased left ventricular mass (LVM) and signs of ventricular remodeling in response to HFD. These studies suggest that SSPN influences phenotype in a sex dependent manner and participates in a network of metabolic genes. New & NoteworthyIn this study the association of the sarcospan protein with human obesity is assessed using in vivo models. Sarcospan-deficient mice of both sexes show an age- dependent influence on adipose tissue biology and glucose handling in response to control and high fat diet. The effect of sarcospan deletion was more pronounced effects in females. Aging reveals susceptibility of SSPN-deficient male mice to increased left ventricular mass.