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The immunosuppressive regulatory T (Treg) cells exert emerging effects on adipose tissue homeostasis and systemic metabolism. However, the metabolic regulation and effector mechanisms of Treg cells in coping with obesogenic insults are not fully understood. We have previously established an indispensable role of the O-linked N-Acetylglucosamine (O-GlcNAc) signaling in maintaining Treg cell identity and promoting Treg suppressor function, via STAT5 O-GlcNAcylation and activation. Here, we investigate the O-GlcNAc transferase (OGT)-STAT5 axis in driving the immunomodulatory function of Treg cells for metabolic homeostasis. Treg cell-specific OGT deficiency renders mice more vulnerable to high-fat diet (HFD)-induced adiposity and insulin resistance. Conversely, constitutive STAT5 activation in Treg cells confers protection against adipose tissue expansion and impaired glucose and insulin metabolism upon HFD feeding, in part by suppressing adipose lipid uptake and redistributing systemic iron storage. Treg cell function can be augmented by targeting the OGT-STAT5 axis to combat obesity and related metabolic disorders.

Scope Trimethylamine‐N‐oxide (TMAO) is a microbiota‐dependent and primarily animal‐protein‐derived proatherogenic metabolite. The ecological impact of pork—the most popular animal protein worldwide—on the human microbiome, and in the physiological context of TMAO and other biogenic amines, remains unknown. Poultry being the recommended heart‐healthier animal protein, we investigated—if pork intake results in inferior‐to‐chicken TMAO‐response while consuming a diet based on the Dietary Guidelines for Americans (DGA). Methods and Results In a randomized, controlled, all‐food‐provided, crossover, feeding trial, healthy adults consumed 156 g day−1 of lean‐pork or chicken (active‐control) as primary proteins. Mixed‐effect modeling shows pork as noninferior to chicken for circulating TMAO response and microbiota‐generated essential TMAO‐precursor—trimethylamine (97.5% CI, n = 36/protein). Markers of lipid metabolism, inflammation and oxidative stress, serum levels of betaine, choline, L‐carnitine, composition and functional‐capability of the microbiota, and association of baseline TMAO‐levels with TMAO‐response (both, r > 0.6, p = 0.0001) are nondistinguishable between the protein groups. TMAO reduction and similar shifts in microbiota and biogenic‐amine signatures postdiet in both groups indicate a background DGA‐effect. Conclusion Unlike extrapolating negative results, this study presents noninferiority‐testing based evidence. Consuming pork as a predominant protein within an omnivorous DGA‐diet does not exacerbate TMAO‐response. Results highlight the importance of understanding protein‐TMAO interactions within dietary patterns.

Objectives Age is a risk factor for chronic diseases—the leading causes of death and disability. An omnivorous diet compared to a plant-based diet was shown to increase blood Trimethylamine-N-oxide (TMAO)—a biogenic amine biomarker for atherosclerosis that may also increase the risk for insulin resistance and certain cancers. Worldwide, pork and chicken are the most popular animal proteins, however, poultry is perceived as healthier. It is unknown if pork intake differentially modifies the TMAO-response than poultry which was investigated here using a non-inferiority study design to avoid any potential negative results. Methods In a randomized, active-controlled, 2-arm-crossover trial (NCT03539666), healthy adults (n = 38/arm, age ≥ 50 y) consumed 156 g/day of lean pork or white-meat chicken as the main protein source as part of an omnivorous diet based on the 2015 USDA dietary guidelines. The feeding arms were matched for food ingredients, nutrients, and energy. Overnight-fasted samples were collected before and after each diet phase. LC/MS with isotope-labeled internal standards and 16S-rDNA sequencing were used for metabolite and microbiome measurements, respectively. Univariate and multivariate data were analyzed using supervised and unsupervised machine learning algorithms in R. Results A non-inferiority of pork to poultry for a circulating TMAO-response (97.5% CI, linear mixed model) was observed for the first time. In addition, global biogenic amine signature (346 metabolites, 95% CI), microbiota-dependent essential TMAO precursor—trimethylamine (97.5% CI), three dietary TMAO substrates (choline, betaine, and L-carnitine) as well as the microbiota composition (95% CI) underlying the observed TMAO-response were not different between the two proteins. TMAO phenotype varied at baseline; a higher baseline circulating TMAO concentration associated with distinct microbiota profiles (all, FDR corrected p < 0.05) and greater TMAO-response (p = 0.0001) independent of the dietary proteins. Conclusions Lean pork does not exacerbate TMAO-risk in omnivores 50 years or older. With 95% of Americans being omnivorous and a third of them fast aging, lean pork increases dietary protein options that may help improve adherence to dietary recommendations for greater healthspan. Funding Sources National Pork Board, National Institute of Food & Agriculture

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