Cannon, Barbara, and Jan Nedergaard. Brown Adipose Tissue: Function and Physiological Significance. Physiol Rev 84: 277–359, 2004; 10.1152/physrev.00015.2003.—The function of brown adipose tissue i...

Brown Adipose Tissue: Function and Physiological Significance

Using positron-emission tomography (PET), we found that cold-induced glucose uptake was increased by a factor of 15 in paracervical and supraclavicular adipose tissue in five healthy subjects. We obtained biopsy specimens of this tissue from the first three consecutive subjects and documented messenger RNA (mRNA) and protein levels of the brown-adipocyte marker, uncoupling protein 1 (UCP1). Together with morphologic assessment, which showed numerous multilocular, intracellular lipid droplets, and with the results of biochemical analysis, these findings document the presence of substantial amounts of metabolically active brown adipose tissue in healthy adult humans.

https://www.nejm.org/doi/pdf/10.1056/NEJMoa0808949

Functional brown adipose tissue in healthy adults.

Adipose tissue, best known for its role in fat storage, can also suppress weight gain and metabolic disease through the action of specialized, heat-producing adipocytes. Brown adipocytes are located in dedicated depots and express constitutively high levels of thermogenic genes, whereas inducible 'brown-like' adipocytes, also known as beige cells, develop in white fat in response to various activators. The activities of brown and beige fat cells reduce metabolic disease, including obesity, in mice and correlate with leanness in humans. Many genes and pathways that regulate brown and beige adipocyte biology have now been identified, providing a variety of promising therapeutic targets for metabolic disease.

/pdf/brown-and-beige-fat-development-function-and-therapeutic-5dt1btf02v.pdf

Brown and beige fat: development, function and therapeutic potential

The molecular origin of standard metabolic rate and thermogenesis in mammals is examined. It is pointed out that there are important differences and distinctions between the cellular reactions that 1) couple to oxygen consumption, 2) uncouple metabolism, 3) hydrolyze ATP, 4) control metabolic rate, 5) regulate metabolic rate, 6) produce heat, and 7) dissipate free energy. The quantitative contribution of different cellular reactions to these processes is assessed in mammals. We estimate that approximately 90% of mammalian oxygen consumption in the standard state is mitochondrial, of which approximately 20% is uncoupled by the mitochondrial proton leak and 80% is coupled to ATP synthesis. The consequences of the significant contribution of proton leak to standard metabolic rate for tissue P-to-O ratio, heat production, and free energy dissipation by oxidative phosphorylation and the estimated contribution of ATP-consuming processes to tissue oxygen consumption rate are discussed. Of the 80% of oxygen consumption coupled to ATP synthesis, approximately 25-30% is used by protein synthesis, 19-28% by the Na(+)-K(+)-ATPase, 4-8% by the Ca2(+)-ATPase, 2-8% by the actinomyosin ATPase, 7-10% by gluconeogenesis, and 3% by ureagenesis, with mRNA synthesis and substrate cycling also making significant contributions. The main cellular reactions that uncouple standard energy metabolism are the Na+, K+, H+, and Ca2+ channels and leaks of cell membranes and protein breakdown. Cellular metabolic rate is controlled by a number of processes including metabolic demand and substrate supply. The differences in standard metabolic rate between animals of different body mass and phylogeny appear to be due to proportionate changes in the whole of energy metabolism. Heat is produced by some reactions and taken up by others but is mainly produced by the reactions of mitochondrial respiration, oxidative phosphorylation, and proton leak on the inner mitochondrial membrane. Free energy is dissipated by all cellular reactions, but the major contributions are by the ATP-utilizing reactions and the uncoupling reactions. The functions and evolutionary significance of standard metabolic rate are discussed.

Cellular energy utilization and molecular origin of standard metabolic rate in mammals

Thermogenic mechanisms in brown fat.

Radioactive microspheres (12–16 μm) were used to measure cardiac output (CO), its fractional distribution, and hence tissue blood flow in conscious, warm-acclimated (WA) or cold-acclimated (CA) whi...

Tissue distribution of cold-induced thermogenesis in conscious warm- or cold-acclimated rats reevaluated from changes in tissue blood flow : The dominant role of brown adipose tissue in the replacement of shivering by nonshivering thermogenesis

The net in vivo uptake or release of free fatty acids glycerol, glucose, lactate, and pyruvate by the interscapular brown adipose tissue (IBAT) of barbital-anesthetized, cold-acclimated rats was de...

Uptake of glucose and release of fatty acids and glycerol by rat brown adipose tissue in vivo

Starvation results in an energy-conserving reduction in metabolic rate that has features of an adaptive response. Tissue and organ sites of this response were investigated by examining the effects of starvation for 5 d on tissue blood flow (microsphere method) and regional arteriovenous O2 differences ((a-v)O2) in conscious rats resting quietly at 28 degrees C. Comparison was with fed and overnight-fasted animals. Whole body resting metabolic rates (MR), colonic temperatures (Tc), and tissue weights were also determined. Quantitative changes in energy expenditure (as O2 consumption) were obtained for two regions: the portal-drained viscera (PDV) and the hindquarters (HQ). Fasting overnight resulted in increased blood flow to white adipose tissue (WAT) and decreased flow to the brain, PDV, testes, and skin; however, MR, Tc, the two regional ((a-v)O2, and the weights of most tissues were not significantly altered. In comparison with overnight fasting, starvation for 5 d resulted in a 13% reduction in body weight, weight loss in many tissues and organs, a 26% reduction in MR, a decline of 0.5 degree C in Tc, decreased (a-v)O2 across both the PDV and HQ, reduced cardiac output, and decreased blood flow to the heart, PDV, skin, WAT, leg muscle, HQ, and the musculoskeletal body as a whole. Utilization of O2 by the PDV and HQ (flow X (a-v)O2) declined by amounts that accounted for 22 and 18%, respectively, of the reduction in MR. The reductions in cardiac output (18%) and heart blood flow (36%) indicate that the heart also made a contribution to energy conservation (roughly estimated as 5%).(ABSTRACT TRUNCATED AT 250 WORDS)

Starvation-induced changes in metabolic rate, blood flow, and regional energy expenditure in rats.

The effects of sham, unilateral, and bilateral surgical denervation of rat interscapular brown adipose tissue (IBAT) on blood flow to the two IBAT pads of cold-acclimated (CA) rats during exposure of the animals to 22 or -6 degrees C and on the noradrenaline (NA) content and total dopamine beta-hydroxylase (DBH) (EC 1.14.17.1) activity of the pads in both warm-acclimated (WA)rats and CA rats were examined. Increase in IBAT blood flow upon cold exposure was taken as an index of sympathetically medicated calorigenesis in the tissue, and decreases in tissue levels of NA and DBH served as indices of the extent of destruction of the sympathetic innervation. At 24 h postsurgery, denervated pads of CA rats, rats, whether from unilaterally or bilaterally denervated IBAT, had less than 3% of the NA, 40-44% of the DBH, and 0% of the 10-fold, cold-induced increase in blood flow measured in intact pads of CA rats with sham-operated or unilaterally denervated IBAT. IBAT bilaterally denervated for 24 h was as responsive in terms of its maximum increase in blood flow during infusion of CA rats with NA as intact IBAT. DBH in denervated pads of both WA rats and CA rats fell to 5% or less of control levels at 2 days postdenervation and remained at these low levels, as did NA, for at least 8 weeks. These results strongly support the longstanding but recently challenged hypothesis that each pad of rat IBAT is independently innervated by sympathetic fibers.

Unilaterality of the sympathetic innervation of each pad of rat interscapular brown adipose tissue

Barbital-sedated, warm-acclimated (WA) or cold-acclimated (CA) rats were infused intravenously with noradrenaline (NA) at doses that elicited graded calorigenic responses. Blood flow (Q) to the various bodies of brown adipose tissue (BAT), the major sites of the NA-induced calorigenesis, was measured with labeled microspheres. The O2 content of arterial blood and of venous blood from interscapular BAT and the concentration of NA in arterial plasma (ANA) were also determined. ANA was linearly related to the dose of NA. Calorigenic response and the Q of total BAT and of separate bodies of BAT were sigmoid functions of ANA. The threshold for calorigenic response or for increased flow to BAT was an ANA of about 2 ng/mL (12 nM), except for some bodies of BAT in CA rats where it was closer to 4 ng/mL. Delivery of O2 to total BAT and calorigenic response were related linearly. The bodies of BAT were heterogeneous in Q per gram and in CA rats the hierarchy in Q per gram changed markedly as ANA and calorigenic res...

Noradrenaline-induced calorigenesis in warm- and cold-acclimated rats: relations between concentration of noradrenaline in arterial plasma, blood flow to differently located masses of brown adipose tissue, and calorigenic response.

David O. Foster

Papers

Tissue distribution of cold-induced thermogenesis in conscious warm- or cold-acclimated rats reevaluated from changes in tissue blood flow : The dominant role of brown adipose tissue in the replacement of shivering by nonshivering thermogenesis

Uptake of glucose and release of fatty acids and glycerol by rat brown adipose tissue in vivo

Starvation-induced changes in metabolic rate, blood flow, and regional energy expenditure in rats.

Unilaterality of the sympathetic innervation of each pad of rat interscapular brown adipose tissue

Noradrenaline-induced calorigenesis in warm- and cold-acclimated rats: relations between concentration of noradrenaline in arterial plasma, blood flow to differently located masses of brown adipose tissue, and calorigenic response.