The role of the brown adipocyte on thermogenesis and energy substrate utilization in brown and and white fat depots

棕色脂肪细胞对棕色和白色脂肪库中产热和能量底物利用的作用

• 批准号: RGPIN-2014-06721
• 负责人: Richard, Denis
• 金额: $ 3.86万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=663314
• 关键词: role; brown; adipocyte; thermogenesis; energy

The brown adipocyte is a cell possessing a tremendous capacity for generating heat (thermogenesis). In small mammals brown adipocytes are found regrouped in discrete brown adipose tissue (BAT) depots known as classical BAT depots. In addition, brown adipocytes can proliferate in white adipose tissue (WAT) under adrenergic stimulation [cold exposure or ß3-adrenergic (ADRB3) stimulation] and peroxisome-proliferator-activated receptor-? (PPAR-?) agonists. These brown adipocytes have been referred to as BRITEs (BRown in whITE [9]) and transform WAT into BEIGE (WAT with beige appearance). The heat-producing capacity of BAT is spectacular; it allows small mammals such as rats and mice to live at temperatures close to the freezing point without shivering. BRITEs and the brown adipocytes of classical BAT expressed uncoupling 1 (UCP1), which confers the brown adipocyte its extraordinary thermogenic ability. BRITEs and classical brown adipocytes are about histologically similar even though they have different developmental origins, distinct molecular phenotypes and potentially different thermogenic capacities to contribute to whole body thermogenesis. Indeed, while the role of BAT in thermogenesis has been demonstrated, that of BEIGE remains enigmatic. More investigations are therefore required to identify the respective contributions of BAT and BEIGE to thermogenesis and energy substrate utilization and metabolism. Furthermore it seems essential to ascertain the molecular phenotype of classical brown adipocytes and BRITEs to ultimately facilitate the delineation of their respective roles (see below).**The goal of the proposed research program is to investigate the role of classical BAT and BEIGE in thermogenesis and energy substrate utilization and metabolism. We propose (as objectives) (1) to investigate the effects of cold exposure, ADRB3 agonism and PPAR-? agonism on BAT and BEIGE thermogenic activity and energy substrate utilization and metabolism; (2) to delineate the thermogenic contribution of BAT and BEIGE; (3) to characterize the molecular phenotypes of BAT and BEIGE. We hypothesize (Obj. 1) that both BAT and BEIGE (to a lesser extent) exhibit increased thermogenic capacity, thermogenic activity as well as increased energy utilization and metabolism following treatments known to enhance their development. We additionally hypothesize (Obj. 2) that (1) the thermogenic contribution of BEIGE increases following treatments known to enhance its development; (2) its total contribution per brown adipocyte is close to that of BAT, and (3) 11C-cetate is a surrogate of BAT and BEIGE metabolism that can be used to quantitatively assess thermogenesis (O2 consumption). Finally, we hypothesize (Obj. 3) that BAT, BEIGE and genuine WAT express selective genes that can be better identified after treatments known to promote BEIGE and BAT developments.**Mice and rats will be used to address the various objectives. They will be subjected to protocols aimed at assessing (1) whole body thermogenic activity and energy substrate utilization and metabolism (PET/CT) (2) tissue thermogenesis (3) molecular phenotypes. **Our research team (R Lecomte and D Richard, in collaboration with A Carpentier) has developed over years a tremendous expertise in brown adipocyte thermogenesis and the measurement of BAT metabolism using PET/CT markers, 11C-acetate (tissue oxidative metabolism), 18FDG (glucose uptake) and 18FTHA (NEFA uptake). The proposed program is likely to reinforce collaborations that have so far led to significant contributions to the field of energy homeostasis. **The program does not focus on biomedical questions but rather on basic biological aspects of BAT that appears to be very appropriate for the NSERC's fields of interest and priorities.

褐色脂肪细胞是一种具有巨大产热能力的细胞。在小型哺乳动物中，棕色脂肪细胞被发现在离散的棕色脂肪组织（BAT）库中重组，称为经典的BAT库。此外，棕色脂肪细胞可以增殖的白色脂肪组织（WAT）下肾上腺素能刺激[冷暴露或β 3-肾上腺素（ADRB 3）刺激]和过氧化物酶体增殖物激活受体-？（过氧化物酶体增殖物受体-？）激动剂这些棕色脂肪细胞被称为BRITE（白色棕色[9]），并将WAT转化为BEIGE（米色外观的WAT）。BAT的产热能力是惊人的;它允许小哺乳动物，如大鼠和小鼠，生活在接近冰点的温度下而不发抖。BRITEs和经典BAT的棕色脂肪细胞表达解偶联1（UCP 1），这赋予棕色脂肪细胞非凡的产热能力。BRITE和经典的棕色脂肪细胞在组织学上是相似的，尽管它们具有不同的发育起源、不同的分子表型和潜在的不同的产热能力以促进全身产热。事实上，虽然BAT在产热中的作用已经得到证明，但BEIGE的作用仍然是个谜。因此，需要进行更多的调查，以确定最佳可得技术和BEIGE各自对产热和能量底物利用和代谢的贡献。此外，似乎有必要确定经典棕色脂肪细胞和BRITE的分子表型，以最终促进其各自作用的描述（见下文）。该研究计划的目标是研究经典BAT和BEIGE在产热和能量底物利用和代谢中的作用。我们建议（作为目标）（1）调查冷暴露，ADRB 3激动和PPAR-？（2）阐明BAT和BEIGE的产热作用;（3）描述BAT和BEIGE的分子表型。我们假设（目标1）BAT和BEIGE（在较小程度上）在已知促进其发育的治疗后表现出产热能力、产热活性以及能量利用和代谢的增加。我们还假设（目标2）：（1）BEIGE的产热作用在已知促进其发育的处理后增加;（2）其每个棕色脂肪细胞的总作用接近BAT;（3）11 C-鲸蜡酸盐是BAT和BEIGE代谢的替代物，可用于定量评估产热作用（O2消耗）。最后，我们假设（目标3）BAT、BEIGE和真正的WAT表达选择性基因，这些基因在已知促进BEIGE和BAT发育的治疗后可以更好地识别。**小鼠和大鼠将用于解决各种目标。他们将接受旨在评估（1）全身产热活性和能量底物利用和代谢（PET/CT）（2）组织产热（3）分子表型的方案。** 我们的研究团队（R Lecomte和D Richard，与A Carpentier合作）多年来在棕色脂肪细胞产热和使用PET/CT标记物测量BAT代谢方面积累了丰富的专业知识，11 C-乙酸盐（组织氧化代谢），18 FDG（葡萄糖摄取）和18 FTHA（NEFA摄取）。拟议中的计划可能会加强迄今为止对能量稳态领域做出重大贡献的合作。** 该计划不侧重于生物医学问题，而是对BAT的基本生物学方面，似乎是非常适合NSERC的兴趣和优先领域。