Abstract
Abstract A chronic low-grade inflammation is considered as a consequence of obesity, and linked with multiple complications. However, it is under-investigated how inflammatory cytokines mediate adipogenesis. This study investigated the role of Tumor Necrosis Factor α (TNF-α) on adipogenes is over high-fat diet feeding. Three groups of wild type or TNF-α-/-mice with the same C57BL/6 genetic background were utilized in this study: wild type fed with a low-fat diet (WT-LFD), wild type fed with a high-fat diet (WT-HFD), and TNF-α-/- fed with a HFD (TNF-HFD). After 16-wk feeding, inflammatory cytokine, Wnt pathway and adipogenesis-related genes were analyzed. HFD feeding increased body weight in both WT-HFD and TNF-HFD groups, but genetic ablation of TNF-α attenuated HFD-induced obesity. In visceral adipose tissues, HFD elevated Wnt/β-catenin signaling, indicated by decreased phospho-GSK3β and active β-catenin, two key components within the Wnt pathway, and dysregulated adipogenesis, indicated by reduced PPARγ/CEBPα expressions. Whereas, the deletion of TNF-α suppressed Wnt-signaling, and restored expressions of adipogenes is-related genes, which were otherwise decreased in the HFD-induced obese animals. These findings demonstrated a critical role of TNF-α in the regulation of Wnt-signaling and adiposity in mice over a HFD feeding, indicating HFD-induced adipocyte dysfunction could be mitigated by targeting TNF-α and Wnt-signaling.
Highlights
It is well-established that obesity, with inflammation as one of the critical mechanisms, linked to a range of chronic diseases such as type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), cardiovascular disease (CVD), and cancer [1]
At 8 weeks of age, animals were divided into 3 groups (26 animals (13 males and 13 females) /group): wild type fed with a low-fat diet (WT-LFD, 10 % of total calorie from fat), wild type fed with a high-fat diet (WT-HFD, 60 % of total calorie from fat), and Tumor Necrosis Factor α (TNF-α)-/- fed with the same highfat diet (TNF-HFD).A high fat diet, which is commonly used to induce obesity, was purchased from Research Diets (HFD: D12492 vs. LFD: D12450B, New Brunswick, NJ)
After 7 weeks, the body weight of the wild type animals fed a high fat diet (WT-HFD) increased to a degree that was significantly higher than the body weight of those animals fed a low fat diet (WT-LFD), whereas a statistical difference was not observed for the TNFα-/-animals (TNF-HFD) until 13 weeks of a high fat diet feeding (p < 0.05)
Summary
It is well-established that obesity, with inflammation as one of the critical mechanisms, linked to a range of chronic diseases such as type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), cardiovascular disease (CVD), and cancer [1]. How inflammatory cytokines reversely mediate adipogenesis is less investigated. To understand this mechanism and prevent chronic over nutrition-induced adipocyte dysfunction represents a promising approach to diminish the epidemic of obesity and its associated medical complications in our society [3,4]. As an endocrine organ, plays an important role in maintaining the whole-body energy metabolism [5]. In order to maintain its function, a constant differentiation of adipocytes (adipogenesis) is necessary in adipose tissue [6]. It is important to understand the regulation of PPARγ expression in obesity, thereby providing feasible av-
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