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

Abstract

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. MFS patients 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 Fbn1mgR/mgR mice and Fbn1C1041G/+ mice with a fibrillin-1 missense mutation. When Fbn1mgR/mgR mice were fed with high fat diet (HFD) for 12 weeks, male mice were heavier than littermate controls (LC), whereas female mice gained less weight compared to LC. Female Fbn1C1041G/+ mice on a HFD for 24 weeks were similarly protected from weight gain. Male Fbn1C1041G/+ mice on HFD demonstrated higher insulin levels, insulin intolerance, circulating levels of cholesterol and high-density lipoproteins. Moreover, male HFD-fed Fbn1C1041G/+ 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) as well as the expression of sterol regulatory element-binding protein 1 (Srebp1) in livers of HFD-fed male Fbn1C1041G/+ mice were elevated. In conclusion, the data demonstrate that male mice of both MFS models are susceptible to HFD-induced obesity and diabetes. Moreover, male Fbn1C1041G/+ 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.

Deficiency of histone variant macroH2A1.1 is associated with sexually dimorphic obesity in mice

“…To investigate the potential epigenetic role specifically of macroH2A1.1 isoform in sex dimorphic obesity and metabolic disturbances, we challenged wild type (Fl/Fl) or macroH2A1.1 knockout (KO) male and female animals with a long-term high fat dietary regimen. We adopted a well-established mouse model of obesity, where young mice (10–12 weeks of age) are fed a HFD (60% energy from lard) 36 – 38 for 12 weeks, after which the animals were sacrificed for further analyses. Interestingly, in male mice there was not difference in basal body weight between Fl/Fl and KO mice (t = 1.240, p = 0.3095) (Fig.…”

“…Compared to their control genotype, macroH2A1.1 KO female mice fed a HFD developed accrued obesity and glucose intolerance, which was accompanied by adipocyte hypertrophy with pro-adipogenic gene expression. The HFD used in our study contains 60% fat from lard, and it is well established to be obesogenic in adult mice in the C57BL/6 background 36 – 38 ; with an approximate fatty acid profile (% of total fat) of 37% saturated, 47% monounsaturated, 16% polyunsaturated. Obesity-related macroH2A1.1 dependent phenotypes using other common HFD remain to be studied.…”

“…The diet consisted of a purified high fat diet used to induce obesity, containing 60% of energy derived from fat (Teklad, TD 06414, Envigo; 36% saturated, 41% monounsaturated, 23% polyunsaturated; 18% protein). This diet allows mice to gain weight consistently and it is frequently used to induce obesity 36 – 38 .…”