Mechanism of obesity suppression by adipose tissue creatine energetics
Bibliographic record
Abstract
The increase in obesity worldwide has led to a surge in the prevalence of type 2 diabetes, cardiovascular disease and many cancers. The capacity of thermogenic (brown and beige) fat to dissipate chemical energy as heat offers tremendous potential to combat obesity. Exploiting thermogenesis to regulate body weight requires a precise molecular understanding of its control at the level of mitochondria. We have previously demonstrated that creatine drives energy expenditure in adipose tissue by stimulating a futile cycle of mitochondrial ATP turnover. Our recent findings show that genetic deletion of the rate‐limiting enzyme of creatine synthesis (Gatm) results in rapid‐onset obesity due to the suppression of elevated energy expenditure that occurs in response to high calorie feeding. This is paralleled by a blunted capacity for β3‐adrenergic activation of metabolic rate. Moreover, abolishing adipocyte creatine uptake, by deleting the creatine transporter (CrT), similarly impairs adrenergic thermogenesis and causes obesity. These results provide strong in vivo genetic support for a role of adipose tissue creatine metabolism in the activation of energy expenditure and the defense against diet‐induced obesity. However, the mechanism underlying creatine‐dependent thermogenesis is not fully understood. We have now identified the primary Creatine Kinase (CK) isoform that controls thermogenic respiration in brown fat. Using quantitative proteomics from purified brown adipocytes and brown adipocyte mitochondria, we find brain‐type CK (B‐CK) to be the most abundant CK in murine brown fat. Surprisingly a subset of B‐CK is targeted to mitochondria. Mitochondria from primary brown adipocytes have robust capacity for creatine‐dependent thermogenic respiration, and knockdown of B‐CK impairs this process. Notably, B‐CK is the most abundance CK isoform in purified human subcutaneous adipocytes and its expression is significantly lower in insulin‐resistant compared to insulin‐sensitive patients. Therefore, B‐CK is the first molecular handle that should result in the identification of additional components regulating creatine‐dependent thermogenesis. In addition, adipose tissue creatine energetics is correlated with healthy glucose homeostasis in humans. Support or Funding Information Canadian Institutes of Health Research postdoctoral fellowship and NIDDK, NIH Pathway to Independence (K99/R00), K99DK114528 (to L.K.) NIH grant (DK31405) and the JPB Foundation (to B.M.S.). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".