propylthiouracil and Glucose-Intolerance

Obesity leads to multiple health problems, including diabetes, fatty liver, and even cancer. Here, we report that urolithin A (UA), a gut-microflora-derived metabolite of pomegranate ellagitannins (ETs), prevents diet-induced obesity and metabolic dysfunctions in mice without causing adverse effects. UA treatment increases energy expenditure (EE) by enhancing thermogenesis in brown adipose tissue (BAT) and inducing browning of white adipose tissue (WAT). Mechanistically, UA-mediated increased thermogenesis is caused by an elevation of triiodothyronine (T3) levels in BAT and inguinal fat depots. This is also confirmed in UA-treated white and brown adipocytes. Consistent with this mechanism, UA loses its beneficial effects on activation of BAT, browning of white fat, body weight control, and glucose homeostasis when thyroid hormone (TH) production is blocked by its inhibitor, propylthiouracil (PTU). Conversely, administration of exogenous tetraiodothyronine (T4) to PTU-treated mice restores UA-induced activation of BAT and browning of white fat and its preventive role on high-fat diet (HFD)-induced weight gain. Together, these results suggest that UA is a potent antiobesity agent with potential for human clinical applications.

Topics: Adipocytes, Brown; Adipocytes, White; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Anti-Obesity Agents; Coumarins; Diet, High-Fat; Energy Metabolism; Fatty Liver; Glucose Intolerance; Insulin Resistance; Maillard Reaction; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Propylthiouracil; Thermogenesis; Triiodothyronine; Weight Gain

During pregnancy, maternal metabolic disease and hormonal imbalance may alter fetal beta cell development and/or proliferation, thus leading to an increased risk for developing type 2 diabetes in adulthood. Although thyroid hormones play an important role in fetal endocrine pancreas development, the impact of maternal hypothyroidism on glucose homeostasis in adult offspring remains poorly understood.. We investigated this using a mouse model of hypothyroidism, induced by administration of an iodine-deficient diet supplemented with propylthiouracil during gestation.. Here, we show that, when fed normal chow, adult mice born to hypothyroid mothers were more glucose-tolerant due to beta cell hyperproliferation (two- to threefold increase in Ki67-positive beta cells) and increased insulin sensitivity. However, following 8 weeks of high-fat feeding, these offspring gained 20% more body weight, became profoundly hyperinsulinaemic (with a 50% increase in fasting insulin concentration), insulin-resistant and glucose-intolerant compared with controls from euthyroid mothers. Furthermore, altered glucose metabolism was maintained in a second generation of animals.. Therefore, gestational hypothyroidism induces long-term alterations in endocrine pancreas function, which may have implications for type 2 diabetes prevention in affected individuals.

Topics: Animals; Antithyroid Agents; Blood Glucose; Cell Proliferation; Diet, High-Fat; Disease Models, Animal; Female; Glucose Intolerance; Hyperinsulinism; Hypothyroidism; Insulin Resistance; Insulin-Secreting Cells; Iodine; Islets of Langerhans; Mice; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Propylthiouracil; Stress, Physiological