Male Marfan mice are predisposed to high-fat diet-induced obesity, diabetes, and fatty liver.

Gene mutations in the extracellular matrix protein fibrillin-1 cause connective tissue disorders including Marfan syndrome (MFS) with clinical symptoms in the cardiovascular, skeletal, and ocular systems. Patients with MFS also exhibit alterations in adipose tissues, which in some individuals leads to lipodystrophy, whereas in others to obesity. We have recently demonstrated that fibrillin-1 regulates adipose tissue homeostasis. Here, we examined how fibrillin-1 abnormality affects metabolic adaptation to different diets. We used two MFS mouse models: hypomorph mice and mice with a fibrillin-1 missense mutation. When mice were fed with high-fat diet (HFD) for 12 wk, male mice were heavier than littermate controls (LCs), whereas female mice gained less weight compared with LCs. Female mice on an HFD for 24 wk were similarly protected from weight gain. Male mice on an HFD demonstrated higher insulin levels, insulin intolerance, circulating levels of cholesterol, and high-density lipoproteins. Moreover, male HFD-fed mice showed a higher liver weight and a fatty liver phenotype, which was reduced to LC levels after orchiectomy. Phosphorylation of protein kinase-like endoplasmic reticulum kinase (PERK) and the expression of sterol regulatory element-binding protein 1 () in livers of HFD-fed male mice were elevated. In conclusion, the data demonstrate that male mice of both the MFS models are susceptible to HFD-induced obesity and diabetes. Moreover, male mice develop a fatty liver phenotype, likely mediated by a baseline increased endoplasmic reticulum stress. In contrast, female MFS mice were protected from the consequence of HFD.