The function and pathology of brown adipose tissue in animals and humans

Abstract

Brown adipose tissue (BAT), an endocrine tissue, is an important regulator of nonshivering thermogenesis, energy metabolism, mitochondrial biogenesis, extracellular matrix (EMA) homeostasis and signaling, and hibernation. There is a paucity of data about BAT response in laboratory animals because BAT has not been routinely included in regulated safety assessment study protocols. We will present information on the structure, function and pathology of BAT, focusing mainly on younger and older rats from an exploratory study set to study BAT and all other tissues over time, from 6 weeks to 96 weeks of age. The energy supply process is stimulated in mammals mainly by hypothermia and by hypoxia and, in primates, by hypoglycemia. Of these, hypothermia is the main stimulus of brown adipocyte (BA) proliferation. Thermogenesis is achieved in BA in the mitochondria (mt), which are 50 to 100 times more abundant in BA than in any other cell type. The mt response involves a membranous protein in the inner membrane, uncoupling protein (UCP1) or thermogenin. Triiodothyronine (T 3) is implicated in the regulation of the UCP1 gene. UCP allows mt to oxidize substrates rapidly without ADP phosphorylation, thus uncoupling oxidation from phosphorylation and promoting instead the dissipation of oxidation energy as heat. Norepinephrine (NEPI) binds to the β3-adrenoreceptor in BA leading to activation of lipoprotein lipase (LPL), which stimulates lipolysis and liberates FFA. Both NEPI and insulin (I) stimulate glucose uptake by BA, and NEPI increases UCP in BA. Nitric oxide (NO) stimulates the biogenesis of mt, redistribution of heat generated by the mt and inhibition of BA proliferation. NO also regulates the binding and releasing of oxygen from hemoglobin (Hgb) and the mt pathway of apoptosis. These effects of NO are mediated by peroxisome proliferator-activated gamma receptor coactivator 1alpha (PPARCA). NO is produced by endothelial NO synthase (eNOS) mainly in BA, but also in the hepatocytes and cells of the zona glomerulosa. PPARCA in turn increases the expression of nuclear respiratory factor-1 (NRF-1) and mitochondrial transcription factor A (mtTFA). Thus, UCP, T3, I, NEPI, NO, PPARCA1, cGMP, eNOS, NRF-1 and mtTFA are all parts of an interactive cascade connecting the BA functions through the EMA of all tissues to controlling the processes of EMA homeostasis and signaling, tissue normoxia and normothermia, apoptosis, proliferation, and differentiation of all cells.