Diet-induced hyperplastic expansion in subcutaneous adipose tissue and protection against adipose progenitor exhaustion in female mice are lost with ovariectomy
Bibliographic record
Abstract
ABSTRACT Background The protection of females against cardiometabolic disease is in part attributable to a tendency for fat accumulation in subcutaneous depots, which promote lipid homeostasis by serving as a metabolic sink. At menopause this protection is lost, and body fat distribution resembles the male-like pattern of visceral adiposity. Adipose progenitor cells (APCs) can be recruited to support adipose expansion in the setting of obesity. Sex differences in diet-induced APC responses may in part explain sexual dimorphism in risk for obesity-associated insulin resistance; however, the role of sex and estrogen in governing APC function remains unclear. Methods Four groups of C57BL/6 mice were assessed: intact males vs. females, and sham vs. ovariectomized (ovx) with or without 17β-estradiol (E2). Adipogenesis was stimulated by rosiglitazone (rosi), while obesity was induced by high fat/fructose diet (HHFD). Flow cytometry quantified the total number of APCs and identify committed preadipocytes by the loss of CD24 expression. Body composition was measured by NMR, while adipose function assessed by measuring circulating adipokines and free fatty acids and lipolysis in adipose explants. Results Despite greater accumulation of fat mass in response to rosi, females were protected against the depletion in subcutaneous APCs and preadipocytes that was observed in rosi-treated males. Similar to intact males, APC and preadipocytes in subcutaneous depots of ovx females were reduced after rosi treatment. The protection of obese females against the development of insulin resistance and adipose dysfunction was lost with ovx, and E2 re-supplementation rescued HFFD- induced APC exhaustion. Exposure to HFFD after discontinuation of rosi exacerbated glucose intolerance in males only. Conclusions Estrogen-mediated hyperplastic expansion in subcutaneous depots permits renewal of the APC pool and preservation of adipose function. PLAIN ENGLISH SUMMARY Despite well-established sex differences in the risk for type 2 diabetes that vary across the lifespan, very little is known regarding sex-specific mechanisms in its pathophysiology. In the setting of obesity, stem cells resident in fat tissue can be recruited for the generation of new fat cells, an important mechanism that maintains metabolic health. It is thought that a reduced availability or dysfunction in fat-residing stem cells is an important pathophysiological event that triggers the onset of obesity-associated type 2 diabetes. Herein, we aimed to determine how sex and estrogen influence stem cell availability and function. Our data show that the ability of fat- residing stem cells to respond to an obesogenic environment is greater in females in an estrogen- dependent manner. Estrogen-dependent stem cell responses to an obesogenic environment may contribute to the protection of females against obesity-induced type 2 diabetes and loss of this protection after menopause. HIGHLIGHTS Sexual dimorphism in activation of adipogenesis by rosiglitazone is mediated by estrogen. Exhaustion of the APC pool occurs in subcutaneous depots of male mice, while estrogen mediates protection of females against APC exhaustion. Preservation of subcutaneous adipose expansion capacity due to renewal of the progenitor pool may contribute to protection of females against obesity-associated insulin resistance.
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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 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
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".