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

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.

Obesity and Fatty Acids Promote Mitochondrial Translocation of STAT3 Through ROS-Dependent Mechanisms.

Obesity promotes the onset and progression of metabolic and inflammatory diseases such as type 2 diabetes. The chronic low-grade inflammation that occurs during obesity triggers multiple signaling mechanisms that negatively affect organismal health. One such mechanism is the persistent activation and mitochondrial translocation of STAT3, which is implicated in inflammatory pathologies and many types of cancers. STAT3 in the mitochondria (mitoSTAT3) alters electron transport chain activity, thereby influencing nutrient metabolism and immune response. PBMCs and CD4+ T cells from obese but normal glucose-tolerant (NGT) middle-aged subjects had higher phosphorylation of STAT3 on residue serine 727 and more mitochondrial accumulation of STAT3 than cells from lean subjects. To evaluate if circulating lipid overabundance in obesity is responsible for age- and sex-matched mitoSTAT3, cells from lean subjects were challenged with physiologically relevant doses of the saturated and monounsaturated fatty acids, palmitate and oleate, respectively. Fatty acid treatment caused robust accumulation of mitoSTAT3 in all cell types, which was independent of palmitate-induced impairments in autophagy. Co-treatment of cells with fatty acid and trehalose prevented STAT3 phosphorylation and mitochondrial accumulation in an autophagy-independent but cellular peroxide-dependent mechanism. Pharmacological blockade of mitoSTAT3 either by a mitochondria-targeted STAT3 inhibitor or ROS scavenging prevented obesity and fatty acid-induced production of proinflammatory cytokines IL-17A and IL-6, thus establishing a mechanistic link between mitoSTAT3 and inflammatory cytokine production.

Regulatory T Cells Control Effector T Cell Inflammation in Human Prediabetes.

A disparate array of plasma/serum markers provides evidence for chronic inflammation in human prediabetes, a condition that is most closely replicated by standard mouse models of obesity and metaflammation. These remain largely nonactionable and contrast with our rich understanding of inflammation in human type 2 diabetes. New data show that inflammatory profiles produced by CD4+ T cells define human prediabetes as a unique inflammatory state. Regulatory T cells (Treg) control mitochondrial function and cytokine production by CD4+ effector T cells (Teff) in prediabetes and type 2 diabetes by supporting T helper (Th)17 or Th1 cytokine production, respectively. These data suggest that Treg control of Teff metabolism regulates inflammation differentially in prediabetes compared with type 2 diabetes. Queries of genes that impact mitochondrial function or pathways leading to transcription of lipid metabolism genes identified the fatty acid importer CD36 as highly expressed in Treg but not Teff from subjects with prediabetes. Pharmacological blockade of CD36 in Treg from subjects with prediabetes decreased Teff production of the Th17 cytokines that differentiate overall prediabetes inflammation. We conclude that Treg control CD4+ T cell cytokine profiles through mechanisms determined, at least in part, by host metabolic status. Furthermore, Treg CD36 uniquely promotes Th17 cytokine production by Teff in prediabetes.