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，棕色脂肪细胞在离散的棕色脂肪组织(BAT)储存库中重新组合，称为经典的BAT储存库。此外，棕色脂肪细胞可在肾上腺素能刺激[冷暴露或3-肾上腺素能(ADRB3)刺激]和过氧化体增殖物激活受体？？的刺激下在白色脂肪组织(WAT)中增殖。(PPAR-？)激动剂。这些棕色脂肪细胞被称为不列颠人(棕色穿白[9])，并将Wat转化为米色(Wat具有米色外观)。蝙蝠的产热能力令人叹为观止；它可以让老鼠等小型哺乳动物在接近冰点的温度下生活，而不会颤抖。英国人和经典蝙蝠的棕色脂肪细胞表达解偶联1(UCP1)，这使得棕色脂肪细胞具有非凡的生热能力。英国人和经典的棕色脂肪细胞在组织结构上大致相似，尽管它们具有不同的发育来源、不同的分子表型和潜在的不同的产热能力，对全身产热做出贡献。事实上，虽然蝙蝠在产热中的作用已经被证明，但米色的作用仍然是个谜。因此，需要更多的研究来确定BAT和BIGE对产热和能量底物利用和代谢的各自贡献。此外，确定经典棕色脂肪细胞和英国人的分子表型似乎是必要的，以最终有助于描述它们各自的角色(见下文)。**拟议研究计划的目标是调查经典BAT和米色在产热和能量底物利用和新陈代谢中的作用。我们建议(作为目标)(1)研究冷暴露、ADRB3激动剂和PPAR-？对BAT和MIGE的发热活性及能量底物的利用和代谢的激活性；(2)描述BAT和BIGE的生热贡献；(3)表征BAT和MIGE的分子表型。我们假设(Obj.1)在已知促进其发育的处理之后，BAT和米色(在较小程度上)都表现出更高的生热能力、生热活性以及更高的能量利用和新陈代谢。我们另外假设(Obj.(2)(1)在已知促进其发育的处理后，米色的生热贡献增加；(2)它对棕色脂肪细胞的总贡献与BAT接近，(3)11C-乙酸酯是BAT和米色代谢的替代品，可用于定量评估生热(O2消耗)。最后，我们假设(Obj.3)蝙蝠、米色和真正的Wat表达选择性基因，在已知促进米色和蝙蝠发育的治疗方法后，可以更好地识别这些基因。**老鼠和大鼠将被用来解决各种目标。他们将接受旨在评估(1)全身产热活动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、11C-乙酸酯(组织氧化代谢)、18FDG(葡萄糖摄取)和18FTHA(NEFA摄取)测量蝙蝠代谢方面积累了丰富的专业知识。拟议中的计划可能会加强迄今已为能源动态平衡领域做出重大贡献的合作。**该计划不关注生物医学问题，而是关注BAT的基本生物学方面，这似乎非常适合NSERC的兴趣和优先领域。

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.