Removal Of Brown Adipose Tissue Research Articles

Mirabegron displays anticancer effects by globally browning adipose tissues

Metabolic reprogramming in malignant cells is a hallmark of cancer that relies on augmented glycolytic metabolism to support their growth, invasion, and metastasis. However, the impact of global adipose metabolism on tumor growth and the drug development by targeting adipose metabolism remain largely unexplored. Here we show that a therapeutic paradigm of drugs is effective for treating various cancer types by browning adipose tissues. Mirabegron, a clinically available drug for overactive bladders, displays potent anticancer effects in various animal cancer models, including untreatable cancers such as pancreatic ductal adenocarcinoma and hepatocellular carcinoma, via the browning of adipose tissues. Genetic deletion of the uncoupling protein 1, a key thermogenic protein in adipose tissues, ablates the anticancer effect. Similarly, the removal of brown adipose tissue, which is responsible for non-shivering thermogenesis, attenuates the anticancer activity of mirabegron. These findings demonstrate that mirabegron represents a paradigm of anticancer drugs with a distinct mechanism for the effective treatment of multiple cancers.

99-OR: Leptin Mediates Postprandial Thermogenesis through a Hypothalamic-Adrenomedullary-BAT Axis

The mechanism by which meal ingestion causes thermogenesis remains unknown. Here we show that refeeding leads to a 10x increase in plasma leptin concentrations associated with a 2.5x increase in plasma catecholamine concentrations in 48h-fasted lean rats. This leptin/catecholamine surge was associated with a 1°C increase in body temperature (BT) (fed 35.9±0.1°C, fasted 35.4±0.0°C, P<0.001; refed 36.4±0.1°C, P<0.001 vs. fasted and P<0.05 vs. fed). Leptin infusion in fasted rats replicated these increases in epinephrine and BT. However, the effect of leptin to increase BT was abrogated in adrenalectomized (ADX) rats following refeeding and leptin infusion. Treatment with a β1-adrenergic antagonist (atenolol) or surgical removal of brown adipose tissue (BAT) also prevented leptin- and refeeding-induced thermogenesis. The effect of refeeding to increase leptin and cause thermogenesis depended on the meal composition: a dextrose meal increased leptin, epinephrine, and BT whereas an isocaloric fat meal did not (AUC P<0.01, 0.05, and 0.01, respectively). Meal thermogenesis was not observed in obese rats, in which fasting plasma leptin failed to fall below the threshold (∼1.8 ng/mL) at which reductions in leptin lowered catecholamine concentrations. In order to examine the potential role for meal thermogenesis to regulate energy balance, we compared rats fed for 10 days with a carbohydrate-rich meal replacement by either two boluses daily or a continuous intragastric infusion. Bolus feeding increased BT and reduced BW gain (bolus feeding 0.1±0.3% weight loss vs. continuous feeding 1.7±0.3% weight gain, P<0.001), an effect abrogated by atenolol. Conclusion: Leptin induces postprandial thermogenesis through stimulation of the hypothalamic-adrenomedullary axis resulting in increased plasma catecholamines, which stimulate BAT through increased β1-adrenergic activity. These results provide a potential mechanism by which time-restricted feeding may improve metabolic health. Disclosure R.J. Perry: Research Support; Self; AstraZeneca. A. Rabin-Court: None. J. Dong: None. K. Lyu: None. X. Li: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc. Advisory Panel; Spouse/Partner; Merck & Co., Inc. Board Member; Self; Novo Nordisk A/S. Consultant; Self; Aegerion Pharmaceuticals, IMetabolic BioPharma Corporation, Longitude Capital, Nimbus Discovery, Inc., Staten Biotechnology B.V. Funding National Institutes of Health (R01DK113984, P30DK059635, T32DK101019, K99/R00CA215315, R01NS087568, UL1TR000142, T32DK007058, R01DK075632, R01DK089044, R01DK096010, R01DK111401)

12,13-diHOME: An Exercise-Induced Lipokine that Increases Skeletal Muscle Fatty Acid Uptake

Circulating factors released from tissues during exercise have been hypothesized to mediate some of the health benefits of regular physical activity. Lipokines are circulating lipid species that have recently been reported to affect metabolism in response to cold. Here, lipidomics analysis revealed that a bout of moderate-intensity exercise causes a pronounced increase in the circulating lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) in male, female, young, old, sedentary, and active human subjects. In mice, both a single bout of exercise and exercise training increased circulating 12,13-diHOME and surgical removal of brown adipose tissue (BAT) negated the increase in 12,13-diHOME, suggesting that BAT is the tissue source for exercise-stimulated 12,13-diHOME. Acute 12,13-diHOME treatment of mice invivo increased skeletal muscle fatty acid uptake and oxidation, but not glucose uptake. These data reveal that lipokines are novel exercise-stimulated circulating factors that may contribute to themetabolic changes that occur with physical exercise.

Partial removal of brown adipose tissue enhances humoral immunity in warm-acclimated Mongolian gerbils ( Meriones unguiculatus)

Temperate rodent species experience marked seasonal fluctuations in environmental temperatures. High thermoregulatory demands during winter usually weaken immune function. Brown adipose tissue (BAT) plays a crucial role in adaptive thermoregulatory process. Thus, we proposed the hypothesis that BAT might participate in the regulation of seasonal changes in immune function. The present study examined the trade-off between thermoregulation and immune function and the potential role of BAT in regulating seasonal changes in immune function in Mongolian gerbils. Specifically, surgical removal of interscapular BAT (34% of total BAT) was performed in male gerbils, and subsequently acclimated to either warm (23 ± 1 °C) or cold (4 ± 1 °C) conditions. Gerbils were then challenged with innocuous antigens and the immune responses were measured. Resting metabolic rate (RMR) and nonshivering thermogenesis (NST) were increased under cold conditions. However, the cost of thermoregulation during cold acclimation did not suppress T-cell mediated immunity and humoral immunity or decrease spleen mass, thymus mass and white blood cells. Partial removal of BAT significantly enhanced humoral immunity in warm-acclimated, but not in cold-acclimated gerbils. T-cell mediated immunity, white blood cells and immune organs were not affected by BAT removal under both warm and cold conditions. Collectively, our results imply that BAT has a suppressive effect on humoral immunity in warm-acclimated gerbils and differential effects of BAT on humoral immunity under different temperatures (e.g., summer and winter) might be benefit to their survival.

Non-shivering thermogenesis and brown adipose tissue in the human new-born infant.

WHEN new-born rabbits are exposed to cold or infused with physiological amounts of noradrenaline, there is a substantial increase in O2 consumption without shivering1. Recently, local heat production has been demonstrated in the large mass of brown adipose tissue found in the interscapular region in the newborn rabbit2. Removal of brown adipose tissue abolishes the increase in O2 consumption on exposure to cold or infusion of noradrenaline3. Heat production is accompanied by a four-fold rise in plasma glycerol and a barely significant rise in plasma-free fatty acids4. Since brown adipose tissue has no glycerol kinase this rise in plasma glycerol is an indication of lipolysis of triglycerides4. The small rise in plasma-free fatty acids suggests that fatty acids are being oxidized locally in brown adipose tissue, with the production of heat. Brown adipose tissue is a very rich source of oxidative enzymes5 and co-enzymes6 and in the new-born rabbit has an in vitro O2 consumption higher even than that of cardiac muscle4.