Non-hematopoietic IL-4Rα expression contributes to fructose-driven obesity and metabolic sequelae

Abstract

Objective The 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. Methods WT, 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. Results We 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. Conclusion Our 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.

Dietary Counseling Aimed at Reducing Sugar Intake Yields the Greatest Improvement in Management of Weight and Metabolic Dysfunction in Children with Obesity

“…The pathways affected by fructose metabolism include insulin resistance [ 29 ], decreased fatty acid oxidation [ 30 , 31 ], and increased hepatic de novo lipogenesis [ 32 , 33 ], all of which contribute to fat accumulation. Mechanistically, these processes lead to inflammation [ 34 ], lipotoxicity [ 35 ], endoplasmic reticulum stress [ 36 ], advanced glycation end products [ 37 ], and others, which have been proposed to be the mediators of metabolic complications. On the other hand, isocaloric fructose restriction reduces insulin resistance [ 38 ], NAFLD [ 39 ], and low-density lipoprotein cholesterol [ 40 , 41 ] in human studies.…”

System biology approaches identified novel biomarkers and their signaling pathways involved in renal cell carcinoma with different human diseases

“…Due to its characteristics, the PI3K/AKT signaling pathway is necessary for optimal metabolism, and its imbalance leads to OB and types 2 diabetes mellitus [ 83 ]. In OB, interleukin-4 and interleukin-13 indicated via the IL-4R modulates adipose tissue lipolysis, insulin sensitivity, and liver fibrosis [ 84 ]. Pre-existing metabolic disorders are linked to a higher risk of RCC and vice versa [ 85 ].…”

Population-enriched innate immune variants may identify candidate gene targets at the intersection of cancer and cardio-metabolic disease

“…Both IL-4Rα and IL13-Rα1 have also been implicated in cancer progression and were recently identified as prognostic indicators in soft-tissue sarcoma patients when present in the nucleus. IL-4 regulates lipid metabolism ( 143 ), and ( 142 ) recent findings highlight an intriguing relationship between non-hematopoietic IL-4Rα activation of a non-canonical signaling pathway that regulates a high-fat, high-carbohydrate diet-driven induction of obesity and impacts the severity of obesity-associated sequelae in mice ( 212 ). Numerous genetic epidemiological studies have also shown that IL4 and IL4R and their gene polymorphisms play important roles in asthma in various populations.…”