Specific Macronutrients Exert Unique Influences on the Adipose-Liver Axis to Promote Hepatic Steatosis in Mice

Abstract

Background & AimsThe factors that distinguish metabolically healthy obesity from metabolically unhealthy obesity are not well understood. Diet has been implicated as a determinant of the unhealthy obesity phenotype, but which aspects of the diet induce dysmetabolism are unknown. The goal of this study was to investigate whether specific macronutrients or macronutrient combinations provoke dysmetabolism in the context of isocaloric, high-energy diets.MethodsMice were fed 4 high-energy diets identical in calorie and nutrient content but different in nutrient composition for 3 weeks to 6 months. The test diets contained 42% carbohydrate (sucrose or starch) and 42% fat (oleate or palmitate). Weight and glucose tolerance were monitored; blood and tissues were collected for histology, gene expression, and immunophenotyping.ResultsMice gained weight on all 4 test diets but differed significantly in other metabolic outcomes. Animals fed the starch-oleate diet developed more severe hepatic steatosis than those on other formulas. Stable isotope incorporation showed that the excess hepatic steatosis in starch-oleate–fed mice derived from exaggerated adipose tissue lipolysis. In these mice, adipose tissue lipolysis coincided with adipocyte necrosis and inflammation. Notably, the liver and adipose tissue abnormalities provoked by starch-oleate feeding were reproduced when mice were fed a mixed-nutrient Western diet with 42% carbohydrate and 42% fat.ConclusionsThe macronutrient composition of the diet exerts a significant influence on metabolic outcome, independent of calories and nutrient proportions. Starch-oleate appears to cause hepatic steatosis by inducing progressive adipose tissue injury. Starch-oleate phenocopies the effect of a Western diet; consequently, it may provide clues to the mechanism whereby specific nutrients cause metabolically unhealthy obesity.

Dietary-Induced Low-Grade Inflammation in the Liver

“…Therefore, in our experiments, the liver of the CD group with normal liver fat-content but high cholesterol showed a liver LGI equal to mice fed with HFD, which is comparable to previous results of HFD vs. carbohydrate-rich diet [ 36 ]. We suggest that starch is the main mediator of the elevated cholesterol content and the pro-inflammatory effects seen in the CD group, which is in line with results of Duwaerts et al [ 37 ], describing a pathogenic effect of diets rich in starch on the liver, independent of calories and nutrient proportions [ 37 ]. From a nutritional point of view, CD as well as HFD are rich in lards, contributing to a pro-inflammatory profile [ 38 ] in both groups.…”

Macronutrients and the Adipose-Liver Axis in Obesity and Fatty Liver

“…Our group showed that sugar + saturated fat, when fed to mice in a ratio of 60:20, induced significantly more DNL, hepatic steatosis, and liver injury than an equivalent combination of sugar + unsaturated fat 56, 57. This synergy was not seen when sugar + saturated fat were fed in a ratio of 40:40 58 …”

“…In fact, MUFA have been reported to promote adipocyte hyperplasia rather than the less desirable cellular enlargement in vivo, in association with blunted expression of inflammasome components and activation of metabolic pathways that portend improved insulin sensitivity 99 . Interestingly, despite the apparently benign nature of dietary MUFA toward hepatocytes and adipocytes in vitro, some studies indicate that MUFA-enriched diets (see Table 1 for ingredients) induce more hepatic steatosis than isocaloric SFA-enriched diets 58, 111, 112. Pertinent to this point, studies from our laboratory showed that mice fed diets containing 40% kcal MUFA in the form of high-oleate sunflower oil for 6 months developed substantial hepatic steatosis coincident with pronounced adipose tissue injury and inflammation 58 .…”

“…Interestingly, despite the apparently benign nature of dietary MUFA toward hepatocytes and adipocytes in vitro, some studies indicate that MUFA-enriched diets (see Table 1 for ingredients) induce more hepatic steatosis than isocaloric SFA-enriched diets 58, 111, 112. Pertinent to this point, studies from our laboratory showed that mice fed diets containing 40% kcal MUFA in the form of high-oleate sunflower oil for 6 months developed substantial hepatic steatosis coincident with pronounced adipose tissue injury and inflammation 58 . In 1 human study, feeding a high concentration of MUFA (44% kcal) for 12 weeks also induced monocyte chemoattractant protein-1 expression in adipose tissue 113 .…”

In NAFLD, You Are What You Eat, Not Simply How Much You Eat

“…In this issue of Cellular and Molecular Gastroenterology and Hepatology , the article by Duwaerts et al 2 is, therefore, a timely publication that addresses the relative contribution of total caloric intake versus dietary nutrient content to the nonalcoholic fatty liver disease (NAFLD) epidemic. The authors used an isocaloric, mouse NAFLD model to investigate the effects of common dietary components on hepatic and adipose tissue lipid metabolism and glucose homeostasis.…”