Cysteine depletion triggers adipose tissue thermogenesis and weight loss

Summary

Human samplesThe participants in this study were part of the CALERIE Phase 2 study68, which was a multicentre, parallel-group, randomized controlled trial by recruitment of non-obese healthy individuals. Overall, 238 adults participated at three different locations: Pennington Biomedical Research Center, Washington University and Tufts University (NCT00427193, registered on ClinicalTrials.gov). Duke University served as a coordinating centre. Participants were randomly assigned to of 25% CR or ad libitum caloric intake for 2 years. CR group participants actually reached 14% of CR1,3. Men were between 21 and 50 years old and women were between 21 and 47 years old. Their body mass index was between 22.0 and 27.9 kg m–2 at the initial visit. Samples were collected at baseline, 1 year and 2 years of intervention. Abdominal subcutaneous adipose tissue biopsy was performed on a portion of CR group participants and used for RNA sequencing and metabolomics in this study. All studies were performed under a protocol approved by the Pennington institutional review board with written informed consent from all participants.MiceAll mice were on a C57BL/6J (B6) genetic background. Cth−/− mice (C57BL/6NTac-Cthtm1a(EUCOMM)Hmgu/Ieg) were purchased from the European Mouse Mutant Cell Repository. Breeding these mice to Flipase transgenic mice from The Jackson Laboratories generated Cthfl/fl mice, which were crossed to Adipoq-cre and Albumin-cre, purchased from Jackson Laboratories. Ucp1−/− and CHOP−/− mice were purchased from The Jackson Laboratories and crossed to Cth−/− mice. Fgf21−/− mice were kindly provided by S. Kliewer (UT Southwestern) as described previously40 and crossed to Cth−/− mice. All mice used in this study were housed in specific-pathogen-free facilities in ventilated cage racks that deliver HEPA-filtered air to each cage with free access to sterile water through a Hydropac system at Yale School of Medicine. Mice were fed ad libitum with a standard vivarium chow (Harl...