Abstract
Higher susceptibility to metabolic disease in male exemplifies the importance of sexual dimorphism in pathogenesis. We hypothesized that the higher incidence of non-alcoholic fatty liver disease in males involves sex-specific metabolic interactions between liver and adipose tissue. In the present study, we used a methionine-choline deficient (MCD) diet-induced fatty liver mouse model to investigate sex differences in the metabolic response of the liver and adipose tissue. After 2 weeks on an MCD-diet, fatty liver was induced in a sex-specific manner, affecting male mice more severely than females. The MCD-diet increased lipolytic enzymes in the gonadal white adipose tissue (gWAT) of male mice, whereas it increased expression of uncoupling protein 1 and other brown adipocyte markers in the gWAT of female mice. Moreover, gWAT from female mice demonstrated higher levels of oxygen consumption and mitochondrial content compared to gWAT from male mice. FGF21 expression was increased in liver tissue by the MCD diet, and the degree of upregulation was significantly higher in the livers of female mice. The endocrine effect of FGF21 was responsible, in part, for the sex-specific browning of gonadal white adipose tissue. Collectively, these data demonstrated that distinctively female-specific browning of white adipose tissue aids in protecting female mice against MCD diet-induced fatty liver disease.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is considered to be one of the most common causes of chronic liver disease and is characterized by fat accumulation without significant alcohol consumption [1]
While male mice demonstrated lower levels of total cholesterol, triglyceride and free fatty acid levels than female, Methionine-choline deficient (MCD) diet did not affect lipid profiles in serum of male and female mice. (Figure 2B) These results indicate that male mice are more susceptible to the progression of NAFLD than female mice
It has been suggested that the interaction between peripheral tissues, mainly adipose tissue and liver tissue, play an important role in the development of NAFLD [35]
Summary
Non-alcoholic fatty liver disease (NAFLD) is considered to be one of the most common causes of chronic liver disease and is characterized by fat accumulation without significant alcohol consumption [1]. The disease progresses to the stages-steatohepatitis and hepatic fibrosis. Methionine-choline deficient (MCD) diet, a wellestablished experimental model of NAFLD in rodents, rapidly produces the clinical pathologies including macrovesicular steatosis, hepatocyte ballooning, focal inflammation, hepatic necrosis, and fibrosis [5]. Choline deficiency causes decreased synthesis of phosphatidylcholine which is required for very low-density lipoprotein (VLDL), followed by lipid accumulation in the liver [6]. Methionine deficiency induces oxidative stress and inflammation by decreased generation of S-adenosylmethionine and glutathione [7]. It has been suggested that an inter-organ mechanism contributes to NAFLD, since a decreased capacity for lipid storage alongside increased lipolysis in adipose tissue trigger ectopic lipid accumulation and lipotoxicity in the livers of MCD diet model mice [9, 10]
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