Differences in Lipogenic Gene Expression and Early Markers of Fatty Liver in C57BL/6J Mice Switched From a 45% Fat Diet to a 15% Fat Diet

Chronic overnutrition, along with a myriad of complex psychosocial and societal factors, is contributing to the global increase in metabolic disorders, including obesity, metabolic syndrome (MetS), and metabolic-associated fatty liver disease (MAFLD). The adipose tissue-liver axis (ATLAS) is a major bodily landscape in which metabolic dysfunction is occurring. The adipose tissue is the primary storage site for triacylglycerols (TAG) and synthesis of inflammatory adipokines; the liver is the key metabolic regulator of lipid and glucose homeostasis. Altered metabolism and insulin resistance (IR) within the ATLAS can cause hepatic steatosis (HS), whereby more macronutrient substrates enter the liver and are stored as TAG. While weight loss is the primary resolution for HS, it is difficult for patients to lose weight and maintain weight loss. However, weight loss alone may not attenuate all metabolic and biochemical dysregulation from NAFLD, as has been observed in models with maintained weight loss but concurrently upregulated lipogenic gene expression. It is hypothesized that increased fatty acid synthesis gene expression in the presence of negative energy balance may be due to an evolutionary pressure to maintain body fat and thus energy stores despite concurrent famine or fasting. As a follow-up to our previous study exploring the effects of diet reversal (DR) in C57BL/6J mice, we wanted to determine whether similar weight loss and HS attenuation, yet lipogenic gene upregulation, will occur in mice given a 45% fat diet for 10 weeks followed by a 15% fat diet for 10 weeks ad libitum. Compared to a 20-week 45% FD group (HFD), DR results in decreased body weight, liver mass, and body fat mass, which is consistent with other studies. Diet reversal in males (though not in females) results in lower adjusted liver weights and body fat percentage but no difference in glucose tolerance by week 20. Diet reversal results in increased hepatic expression of mRNA associated with de novo lipogenesis, fatty acid uptake, and beta-oxidation, suggesting transcription associated with overall higher liver metabolism than HFD. With the addition of a 20-week 15% FD (Chow) group, we found that DR body composition is nonsignificant, but that DR hepatic mRNA expression of de novo lipogenesis, fatty acid oxidation, and glucose metabolism is higher than Chow. Unexpectedly, male and female HFD livers broadly had the lowest mRNA expression of DNL transcription factor ChREBP and FATP5, whereas male Chow livers had the highest mRNA expression of FASN and SCD1 and female Chow livers have the highest FATP5.

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