Abstract
ObjectiveThe risks of excess sugar intake in addition to high-fat diet consumption on immunopathogenesis of obesity-associated metabolic diseases are poorly defined. Interleukin-4 (IL-4) and IL-13 signaling via IL-4Rα regulates adipose tissue lipolysis, insulin sensitivity, and liver fibrosis in obesity. However, the contribution of IL-4Rα to sugar rich diet-driven obesity and metabolic sequelae remains unknown.MethodsWT, IL-4Rα-deficient (IL-4Rα−/−) and STAT6-deficient mice (STAT6−/−) male mice were fed low-fat chow, high fat (HF) or HF plus high carbohydrate (HC/fructose) diet (HF + HC). Analysis included quantification of: (i) body weight, adiposity, energy expenditure, fructose metabolism, fatty acid oxidation/synthesis, glucose dysmetabolism and hepatocellular damage; (ii) the contribution of the hematopoietic or non-hematopoietic IL-4Rα expression; and (iii) the relevance of IL-4Rα downstream canonical STAT6 signaling pathway in this setting.ResultsWe show that IL-4Rα regulated HF + HC diet-driven weight gain, whole body adiposity, adipose tissue inflammatory gene expression, energy expenditure, locomotor activity, glucose metabolism, hepatic steatosis, hepatic inflammatory gene expression and hepatocellular damage. These effects were potentially, and in part, dependent on non-hematopoietic IL-4Rα expression but were independent of direct STAT6 activation. Mechanistically, hepatic ketohexokinase-A and C expression was dependent on IL-4Rα, as it was reduced in IL-4Rα-deficient mice. KHK activity was also affected by HF + HC dietary challenge. Further, reduced expression/activity of KHK in IL-4Rα mice had a significant effect on fatty acid oxidation and fatty acid synthesis pathways.ConclusionOur findings highlight potential contribution of non-hematopoietic IL-4Rα activation of a non-canonical signaling pathway that regulates the HF + HC diet-driven induction of obesity and severity of obesity-associated sequelae.
Highlights
Obesity is a major risk factor for development of common, serious medical conditions including low-grade chronic inflammation, insulin resistance, type II diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) [1]
6–8 weeks old mice were started on a diet and were fed either an autoclaved low-fat chow diet food (LAB Diet #5010 (CD); calories provided by carbohydrates (58%), fat (13%) and protein (29%), irradiated high-fat diet (HF; Research Diets #D12492; 20% protein Casein, Lactic, 30 Mesh, Cystine, L; 20% carbohydrate, Lodex 10, Sucrose, Fine Granulated; Fiber; and 60% of calories from fat, Lard, Soybean Oil, USP; Mineral mix S10026B; Vitamin Choline Bitartrate and mix V10001C; energy density 5.21 Kcal/g) or a high-fat high carbohydrate diet (HF Research Diets #D12492i + HC drinking water [HF + HC])
As fructose is processed by the liver, we examined if hematopoietic or non-hematopoietic IL-4Rα was required for modulation of HF + HC diet dependent phenotypes
Summary
Obesity is a major risk factor for development of common, serious medical conditions including low-grade chronic inflammation, insulin resistance, type II diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) [1]. Over the last few decades, intake of carbohydrates via sugar sweetened food coupled with high-fat (HF) diet consumption has greatly increased. While the general effects of HF diet feeding in experimental models of obesity are well understood, risks of excess sugar (e.g., glucose, sucrose, fructose) intake in addition to HF diet consumption are not well defined. Like HF diet, increased consumption of sugars, high-fructose containing goods, promotes obesity-related sequelae [2]. Both fructose and glucose are 6-carbon sugars, cellular metabolism of these sugars is divergent. Ubiquitous cellular processing of glucose in the body triggers strong insulin secretion. Fructose is mainly processed by the liver and only triggers minor insulin secretion. Fructose potentially promotes hepatic triglyceride (TG) accumulation, hepatic de novo lipogenesis (DNL) [3], contributes to (hepatic) insulin resistance [4], and causes mitochondrial dysfunction and inflammation [5, 6]
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