2021 Diabetes Obes Metab

Sachs S, Niu L, Geyer P, Jall S, Kleinert M, Feuchtinger A, Stemmer K, Brielmeier M, Finan B, DiMarchi RD, Tschöp MH, Wewer Albrechtsen N, Mann M, Müller TD, Hofmann SM.

Plasma proteome profiles treatment efficacy of incretin dual agonism in diet-induced obese female and male mice.

2019 American Journal of Physiology-Endocrinology and Metabolism

Sachs S, Zarini S, Kahn DE, Harrison KA, Perreault L, Phang T, Newsom SA, Strauss A, Kerege A, Schoen JA, Bessesen DH, Schwarzmayr T, Graf E, Lutter D, Krumsiek J, Hofmann SM, Bergman BC

Intermuscular adipose tissue (IMAT) directly modulates skeletal muscle insulin sensitivity in humans.

2013 Circulation

Lehti M, Donelan E, Abplanalp W, Al-Massadi O, Habegger KM, Weber J, Ress C, Mansfeld J, Somvanshi S, Trivedi C, Keuper M, Ograjsek T, Striese C, Cucuruz S, Pfluger PT, Krishna R, Gordon SM, Silva RA, Luquet S, Castel J, Martinez S, D'Alessio D, Davidson WS, Hofmann SM

High-density lipoprotein maintains skeletal muscle function by modulating cellular respiration in mice.

2023 Diabetologia

Lutter D, Sachs S, Walter M, Kerege A, Perreault L, Kahn DE, Wolide AD, Kleinert M, Bergman BC, Hofmann SM

Skeletal muscle and intermuscular adipose tissue gene expression profiling identifies new biomarkers with prognostic significance for insulin resistance progression and intervention response

Aims/hypothesis Although insulin resistance often leads to type 2 diabetes mellitus, its early stages are often unrecognised, thus reducing the probability of successful prevention and intervention. Moreover, treatment efficacy is affected by the genetics of the individual. We used gene expression profiles from a cross-sectional study to identify potential candidate genes for the prediction of diabetes risk and intervention response. Methods Using a multivariate regression model, we linked gene expression profiles of human skeletal muscle and intermuscular adipose tissue (IMAT) to fasting glucose levels and glucose infusion rate. Based on the expression patterns of the top predictive genes, we characterised and compared individual gene expression with clinical classifications using k-nearest neighbour clustering. The predictive potential of the candidate genes identified was validated using muscle gene expression data from a longitudinal intervention study. Results We found that genes with a strong association with clinical measures clustered into three distinct expression patterns. Their predictive values for insulin resistance varied substantially between skeletal muscle and IMAT. Moreover, we discovered that individual gene expression-based classifications may differ from classifications based predominantly on clinical variables, indicating that participant stratification may be imprecise if only clinical variables are used for classification. Of the 15 top candidate genes, ST3GAL2, AASS, ARF1 and the transcription factor SIN3A are novel candidates for predicting a refined diabetes risk and intervention response. Conclusion/interpretation Our results confirm that disease progression and successful intervention depend on individual gene expression states. We anticipate that our findings may lead to a better understanding and prediction of individual diabetes risk and may help to develop individualised intervention strategies.

2023 Cell Metabolism

Becker M, Joseph SS, Garcia-Carrizo F, Tom RZ, Opaleva D, Serr I, Tschöp MH, Schulz TJ, Hofmann SM, Daniel C

Regulatory T cells require IL6 receptor alpha signaling to control skeletal muscle function and regeneration

Muscle-residing regulatory T cells (Tregs) control local tissue integrity and function. However, the molecular interface connecting Treg-based regulation with muscle function and regeneration remains largely unexplored. Here, we show that exercise fosters a stable induction of highly functional muscle-residing Tregs with increased expression of amphiregulin (Areg), EGFR, and ST2. Mechanistically, we find that mice lacking IL6Rα on T cells (TKO) harbor significant reductions in muscle Treg functionality and satellite and fibro-adipogenic progenitor cells, which are required for muscle regeneration. Using exercise and sarcopenia models, IL6Rα TKO mice demonstrate deficits in Tregs, their functional maturation, and a more pronounced decline in muscle mass. Muscle injury models indicate that IL6Rα TKO mice have significant disabilities in muscle regeneration. Treg gain of function restores impaired muscle repair in IL6Rα TKO mice. Of note, pharmacological IL6R blockade in WT mice phenocopies deficits in muscle function identified in IL6Rα TKO mice, thereby highlighting the clinical implications of the findings.