T cells dominate peripheral inflammation in a cross‐sectional analysis of obesity‐associated diabetes

Abstract

Objective Myeloid cells dominate metabolic disease‐associated inflammation (metaflammation) in mouse obesity, but the contributions of myeloid cells to the peripheral inflammation that fuels sequelae of human obesity are untested. This study used unbiased approaches to rank contributions of myeloid and T cells to peripheral inflammation in people with obesity across the spectrum of metabolic health. Methods Peripheral blood mononuclear cells (PBMCs) from people with obesity with or without prediabetes or type 2 diabetes were stimulated with T cell‐targeting CD3/CD28 or myeloid‐targeting lipopolysaccharide for 20 to 72 hours to assess cytokine production using Bio‐Plex. Bioinformatic modeling ranked cytokines with respect to their predictive power for metabolic health. Intracellular tumor necrosis factor α was quantitated as a classical indicator of metaflammation. Results Cytokines increased over 72 hours following T cell‐, but not myeloid‐, targeted stimulation to indicate that acute myeloid inflammation may shift to T cell inflammation over time. T cells contributed more tumor necrosis factor α to peripheral inflammation regardless of metabolic status. Bioinformatic combination of cytokines from all cohorts, stimuli, and time points indicated that T cell‐targeted stimulation was most important for differentiating inflammation in diabetes, consistent with previous identification of a mixed T helper type 1/T helper type 17 cytokine profile in diabetes. Conclusions T cells dominate peripheral inflammation in obesity; therefore, targeting T cells may be an effective approach for prevention/management of metaflammation.

A blunted TH17 cytokine signature in women with mild cognitive impairment: insights from inflammatory profiling of a community-based cohort of older adults

“…5E and F ), consistent with cytokine outcomes in other inflammatory diseases we have studied. 25-28 These data add to the growing appreciation that steady-state plasma cytokine levels lack the discriminative potential to detect disease-associated changes in circulating immune cell populations that could be actionable.…”

“… 44 , 45 A growing body of evidence also finds that systemic inflammatory conditions, such as Type 2 diabetes and healthy ageing, have elevated T H 17 responses compared with healthy individuals. 25-28 , 36 From depression to Parkinson’s disease and beyond, the brain has been described to have signatures of T H 17-related inflammation. 20 , 39 , 46 This is also true for AD, where prior reports link T H 17 responses in the brain to AD-related pathology in people and animals.…”

Insulin and IGF-1 have both overlapping and distinct effects on CD4+ T cell mitochondria, metabolism, and function

“…This suggests that nutritional status communicated to T cells via changes in insulin and IGF-1 hormone levels results in a metabolic and functional program that is persistent and maintained. This has clinical relevance, as both insulin and free IGF-1 levels are increased in individuals with obesity, and T cells have been found to dominate peripheral inflammation in obesity in human studies, with Th17 cells having a particularly prominent role 30 – 32 .…”

Effect of Indian gooseberry extract on improving methylglyoxal-associated leptin resistance in peripheral tissues of high-fat diet-fed rats

“…Oxidative stress and inflammation are key factors in obesity and obesity-related metabolic disorder diseases [ 21 ]. Recently, a report revealed that peripheral T cells secrete TNF-α to contribute to peripheral inflammation and consequently trigger obesity-associated diabetes [ 23 ], indicating that peripheral inflammation dominates the evolution of obesity-related metabolic diseases. Diet and obesity-induced MG production have been documented to be linked to metabolic disease without a deep investigation of the underlying mechanism [ 13 , 24 ].…”