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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 Fbn1<jats:sup>mgR\/mgR<\/jats:sup> mice and Fbn1<jats:sup>C1041G\/+<\/jats:sup> mice with a fibrillin-1 missense mutation. When Fbn1<jats:sup>mgR\/mgR<\/jats:sup> 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 Fbn1<jats:sup>C1041G\/+<\/jats:sup> mice on an HFD for 24 wk were similarly protected from weight gain. Male Fbn1<jats:sup>C1041G\/+<\/jats:sup> mice on an HFD demonstrated higher insulin levels, insulin intolerance, circulating levels of cholesterol, and high-density lipoproteins. Moreover, male HFD-fed Fbn1<jats:sup>C1041G\/+<\/jats:sup> 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 ( Srebp1) in livers of HFD-fed male Fbn1<jats:sup>C1041G\/+<\/jats:sup> 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 Fbn1<jats:sup>C1041G\/+<\/jats:sup> mice develop a fatty liver phenotype, likely mediated by a baseline increased endoplasmic reticulum stress. 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