RESUMO
OBJECTIVE: Obesity represents a major risk factor for the development of type 2 diabetes mellitus, atherosclerosis and certain cancer entities. Treatment of obesity is hindered by the long-term maintenance of initially reduced body weight, and it remains unclear whether all pathologies associated with obesity are fully reversible even upon successfully maintained weight loss. METHODS: We compared high fat diet-fed, weight reduced and lean mice in terms of body weight development, adipose tissue and liver insulin sensitivity as well as inflammatory gene expression. Moreover, we assessed similar parameters in a human cohort before and after bariatric surgery. RESULTS: Compared to lean animals, mice that demonstrated successful weight reduction showed increased weight gain following exposure to ad libitum control diet. However, pair-feeding weight-reduced mice with lean controls efficiently stabilized body weight, indicating that hyperphagia was the predominant cause for the observed weight regain. Additionally, whereas glucose tolerance improved rapidly after weight loss, systemic insulin resistance was retained and ameliorated only upon prolonged pair-feeding. Weight loss enhanced insulin action and resolved pro-inflammatory gene expression exclusively in the liver, whereas visceral adipose tissue displayed no significant improvement of metabolic and inflammatory parameters compared to obese mice. Similarly, bariatric surgery in humans (n = 55) resulted in massive weight reduction, improved hepatic inflammation and systemic glucose homeostasis, while adipose tissue inflammation remained unaffected and adipocyte-autonomous insulin action only exhibit minor improvements in a subgroup of patients (42%). CONCLUSIONS: These results demonstrate that although sustained weight loss improves systemic glucose homeostasis, primarily through improved inflammation and insulin action in liver, a remarkable obesogenic memory can confer long-term increases in adipose tissue inflammation and insulin resistance in mice as well as in a significant subpopulation of obese patients.
RESUMO
T47D-ERß breast cancer cells with tetracycline-dependent ERß expression and constant ERα expression can be used to investigate effects of varying ERα/ERß ratios on estrogen-induced cellular responses. This study defines conditions at which ERα/ERß ratios in T47D-ERß cells best mimic ERα/ERß ratios in breast and other estrogen-sensitive tissues in vivo in rat as well as in human. Protein and mRNA levels of ERα and ERß were analyzed in T47D-ERß cells exposed to a range of tetracycline concentrations and compared to ERα and ERß levels found in breast, prostate, and uterus from rat and human origin. The ERα/ERß ratio in T47D-ERß cells exposed to >150ng/ml tetracycline is comparable to the ratio found in rat mammary gland and in human breast tissue. The ERα/ERß ratio of other estrogen-sensitive rat and human tissues can also be mimicked in T47D-ERß cells. The ERα/ERß ratio found in MCF-7 and native T47D breast cancer cell lines did not reflect ratios in analyzed rat and human tissues, which further supports the use of T47D-ERß cells as model for estrogen-responsive tissues. Using 17ß-estradiol and the T47D-ERß cells under the conditions defined to mimic various tissues it could be demonstrated how these different tissues vary in their proliferative response.