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

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，棕色脂肪细胞在肾上腺素能刺激[冷暴露或ß - 3-肾上腺素能（ADRB3）刺激]和过氧化物酶体增殖因子激活受体-？(PPAR - ?)受体激动剂。这些棕色脂肪细胞被称为BRITEs（白色[9]中的棕色），并将WAT转化为BEIGE（外观为米黄色）。BAT的产热能力惊人；它能让老鼠等小型哺乳动物在接近冰点的温度下生存而不发抖。BRITEs和经典BAT的棕色脂肪细胞表达解偶联1 (uncoupling 1, UCP1)，这赋予了棕色脂肪细胞非凡的产热能力。BRITEs和经典棕色脂肪细胞在组织学上是相似的，尽管它们有不同的发育起源、不同的分子表型和可能不同的产热能力来促进全身产热。事实上，虽然BAT在产热中的作用已经得到证实，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BEIGE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BRITEs的分子表型似乎至关重要，以最终促进它们各自作用的描述（见下文）。

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.