The obesity-related pathology and Th17 cells

Abstract

Chronic inflammation associated with obesity plays a major role in the development of metabolic diseases, cancer, and autoimmune diseases. Among Th subsets, Th17 cells are involved in the pathogenesis of autoimmune disorders such as psoriasis, rheumatoid arthritis, inflammatory bowel disease, steroid-resistant asthma, and multiple sclerosis. Accumulating data suggest that reciprocal interactions between the metabolic systems and immune system play pivotal roles in the pathogenesis of obesity-associated diseases. We herein outline the developing principles in the control of T cell differentiation and function via their cellular metabolism. Also discussed are recent findings that changes in the intracellular metabolism, including fatty acid metabolism, affect the Th17 cell function in obese individuals. Finally, we will also highlight the unique molecular mechanism involved in the activation of retinoid-related orphan receptor-gamma-t (RORγt) by intracellular metabolism and discuss a new therapeutic approach for treating autoimmune disorders through the inhibition of RORγt.

Keywords: ACC1; Chronic inflammation; Fatty acid metabolism; Obesity; RORγt activation; Th17 cells.

Fig. 1

Obesity-associated diseases, and immune system-metabolic system interactions in obese environment. Obesity-induced inflammation contributes to the development of many chronic inflammatory conditions including type 2 diabetes, atherosclerosis, arthritis, steroid-resistant asthma and some forms of cancer. Obesity affects greater changes of leukocyte character in adipose tissue and periphery

Fig. 2

Obesity drives Th17 cell differentiation via the induction of ACC1-RORγt pathway. Left in the healthy lean donor, the expression level of ACC1 and subsequent fatty acid biosynthesis are moderate, and thereby RORγt activation is steady, therefore, Th17 cell differentiation was well controlled. Right in obese patients, the expression of ACC1 is increased and fatty acids are vigorously synthesized, thereby RORγt activation and Th17 cell differentiation were promoted

Fig. 3

Metabolic signatures in naïve resting and activated T cells. To fulfill the energetic requirements associated with activation and rapid proliferation, T cells switch their metabolic signatures from energetically quiescent to activated. Naïve T cells generate ATP mainly by breaking down glucose, fatty acids, and amino acids to fuel oxidative phosphorylation (OXPHOS). In contrast, activated T cells are highly dependent on aerobic glycolysis and glutaminolysis to supply the ATP and other intermediate metabolites. Only two molecules of ATP are generated per molecule of glucose through this pathway, whereas OXPHOS generates up to 36 ATP molecules per molecule of glucose

Fig. 4

Summary of metabolic pathways required for T cell differentiation. Metabolic reprogramming towards an anabolic phenotype during T cell activation is regulated by several signaling pathways and transcription factors. Myc, a critical transcription factor for cell growth and proliferation, controls activation-induced glycolysis and glutaminolysis via the transactivation of key enzymes in these pathways in activated T cells. Hif1α, another transcription factor for glycolysis, selectively regulates glycolysis and effector function in differentiating Th17 cells. SREBPs play an essential role in metabolic reprogramming in response to mitogenic stimulation in activated CD8 T cells through the control of lipid biosynthesis

Fig. 5

ACC1-induced fatty acid biosynthesis is required for the ligand-dependent RORγt activation during Th17 cell differentiation. In addition to oxysterols from sterol biosynthetic process, fatty acid metabolic products from a monounsaturated fatty acid synthesized by ACC1 are required for the function of RORγt and may work as an endogenous ligand for RORγt in differentiating Th17 cells. Activated RORγt and p300 function cooperatively and facilitate chromatin remodeling at the Il17 or other Th17-associated gene loci. MUFA mono unsaturated fatty acid