Hepatic Igf1-Deficiency Protects Against Atherosclerosis in Female Mice

Abstract

Atherosclerosis is the leading cause of cardiovascular disease (CVD) with distinct sex-specific pathogenic mechanisms that are poorly understood. Aging, a major independent risk factor of atherosclerosis, correlates with a decline in circulating insulin-like growth factor-1 (IGF-1). However, the precise effects of Igf1 on atherosclerosis remain unclear. In the present study, we assessed the essential role of hepatic Igf1, the major source of circulating IGF-1, in atherogenesis. We generated hepatic Igf1-deficient atherosclerosis-prone ApoE null mice (L-Igf1 -/-ApoE -/-) using the Cre-loxP system driven by the Albumin promoter. Starting at 6 weeks of age, these mice along with littermate controls, separated into male and female groups, were placed on an atherogenic diet for 18-19 weeks. We show that hepatic Igf1-deficiency led to atheroprotection with reduced plaque macrophages in females, without significant effects in males. This protection in atherosclerosis in females was associated with increased subcutaneous adiposity with impaired lipolysis. Moreover, this impaired lipid homeostasis was associated with disrupted adipokine secretion with reduced circulating IL-6 levels. Together, our data show that endogenous hepatic Igf1 plays a sex-specific regulatory role in atherogenesis potentially through athero-promoting effects of adipose tissue-derived IL-6 secretion. These data provide potential novel sex-specific mechanisms in the pathogenesis of atherosclerosis.