Dietary fat intake promotes the development of hepatic steatosis independently from excess caloric consumption in a murine model

Abstract

Background Non-alcoholic fatty liver disease (NAFLD) results from over-consumption and is a significant and increasing cause of liver failure. The type of diet that is conducive to the development of this disease has not been established and evidence-based treatment options are currently lacking. We hypothesized that the onset of hepatic steatosis is linked to the consumption of a diet with a high fat content, rather than related to excess caloric intake. In addition, we also hypothesized that fully manifested hepatic steatosis could be reversed by reducing the fat percentage in the diet of obese mice. Methods C57Bl/6J male mice were either fed a purified rodent diet containing 10% fat or a diet with 60% of calories derived from fat. A pair-feeding design was used to distinguish the effects of dietary fat content and caloric intake on dietary-induced hepatic lipid accumulation and associated injury. Livers were analyzed by quantitative RT-PCR for lipid metabolism-related gene expression. Results After 9 weeks, mice on the 60% fat diet exhibited more weight gain, insulin resistance and hepatic steatosis, compared to mice on a 10% fat diet with equal caloric intake. Furthermore, mice with established metabolic syndrome at 9 weeks showed reversal of hepatic steatosis, insulin resistance and obesity when switched to a 10% fat diet for an additional 9 weeks, independent of caloric intake. Quantitative RT-PCR revealed that transcripts related to both de novo lipogenesis and increased uptake of free fatty acids were significantly upregulated in mice pair-fed a 60% fat diet, compared to 10% fat-fed animals. Conclusion Dietary fat content, independent from caloric intake, is a crucial factor in the development of hepatic steatosis, obesity and insulin resistance in the C57Bl/6J diet-induced obesity model caused by increased uptake of free fatty acids and de novo lipogenesis. In addition, once established, all these features of the metabolic syndrome can be successfully reversed after switching obese mice to a diet low in fat. Low fat diets deserve attention in the investigation of a potential treatment of patients with NAFLD.

Adipose tissue metabolism and inflammation are differently affected by weight loss in obese mice due to either a high-fat diet restriction or change to a low-fat diet

“…These data strongly suggest that in particular the lowering of energy intake, and not so much the lowering of fat intake, is of primary importance to obtain beneficial metabolic effects of a diet intervention. Our results, however, contrast with previous studies showing that when HFD is restricted to the caloric intake of LFD fed mice, insulin resistance and hepatic steatosis are not prevented (de Meijer et al 2010;Petro et al 2004). The lack of more pronounced effects of the LFD may be due to a stronger decrease in energy intake during HFD restriction compared to the LFD (even though fat intake was higher in HFD-CR).…”

Dietary restriction of mice on a high-fat diet induces substrate efficiency and improves metabolic health

“…Two previous studies, in fact, reported unfavorable effects in mice that were pair-fed on a HF diet to match the caloric intake of mice on a low-fat diet. A certain iso-caloric treatment was found to result in a decrease in insulin sensitivity in the restricted HF group (Petro et al 2004), whereas a second study reported that HF pair-fed mice develop insulin resistance, hepatic steatosis, and obesity (de Meijer et al 2010). The diets used in both studies, however, contained almost twice as much energy available from fat compared with the diet we used in our study (58 and 60% energy from fat, compared with 30%), which might have evoked a different coping strategy.…”

“…Most studies examining the effects of DR, however, have been performed in standard rodent diets that are characterized by a low-fat content (7-9% energy from fat). Only few studies focused on the effect of DR using high-fat diets (HF-DR; Petro et al 2004, Kalupahana et al 2011, de Meijer et al 2010, which is, in fact, more relevant to the current dietary status in most developed countries.…”

GLP2: an underestimated signal for improving glycaemic control and insulin sensitivity

“…Mouse liver expresses GLP2R (El-Jamal et al 2014); however, nothing is known about other species, including humans. Moreover, fatty liver is strongly associated with insulin resistance (Asrih & Jornayvaz 2013), and non-alcoholic hepatic steatosis has been reported in HFD-fed mice (de Meijer et al 2010, Fraulob et al 2010. Indeed, in HFD-fed mice, chronic treatment with GLP2 (3-33) aggravates dyslipidaemia and hepatic lipid accumulation.…”