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

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

Obesity results when energy intake exceeds energy expenditure Naturally occurring genetic mutations, as well as ablative lesions, have shown that the brain regulates both aspects of energy balance and that abnormalities in energy expenditure contribute to the development of obesity Energy can be expended by performing work or producing heat (thermogenesis) Adaptive thermogenesis, or the regulated production of heat, is influenced by environmental temperature and diet Mitochondria, the organelles that convert food to carbon dioxide, water and ATP, are fundamental in mediating effects on energy dissipation Recently, there have been significant advances in understanding the molecular regulation of energy expenditure in mitochondria and the mechanisms of transcriptional control of mitochondrial genes Here we explore these developments in relation to classical physiological views of adaptive thermogenesis

Towards a molecular understanding of adaptive thermogenesis.

The mitochondrial uncoupling protein (UCP) in the mitochondrial inner membrane of mammalian brown adipose tissue generates heat by uncoupling oxidative phosphorylation1. This process protects against cold2 and regulates energy balance3. Manipulation of thermogenesis could be an effective strategy against obesity4–9. Here we determine the role of UCP in the regulation of body mass by targeted inactivation of the gene encoding it. We find that UCP-deficient mice consume less oxygen after treatment with a β3-adrenergic-receptor agonist and that they are sensitive to cold, indicating that their thermo-regulation is defective. However, this deficiency caused neither hyperphagia nor obesity in mice fed on either a standard or a high-fat diet. We propose that the loss of UCP may be compensated by UCP2, a newly discovered homologue of UCP; this gene is ubiquitously expressed and is induced in the brown fat of UCP-deficient mice.

Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese

Brown adipose tissue, because of its capacity for uncoupled mitochondrial respiration, has been implicated as an important site of facultative energy expenditure. This has led to speculation that this tissue normally functions to prevent obesity. Attempts to ablate or denervate brown adipose tissue surgically have been uninformative because it exists in diffuse depots and has substantial capacity for regeneration and hypertrophy. Here we have used a transgenic toxigene approach to create two lines of transgenic mice with primary deficiency of brown adipose tissue. At 16 days, both lines have decreased brown fat and obesity. In one line, brown fat subsequently regenerates and obesity resolves. In the other line, the deficiency persists and obesity, with its morbid complications, advances. Obesity develops in the absence of hyperphagia, indicating that brown fat deficient mice have increased metabolic efficiency. As obesity progresses, transgenic animals develop hyperphagia. This study supports a critical role for brown adipose tissue in the nutritional homeostasis of mice.

Development of obesity in transgenic mice after genetic ablation of brown adipose tissue

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

Barbital-sedated, cold-acclimated (CA) or warm-acclimated (WA) rats were given different doses and combinations of noradrenaline, theophylline, and the adrenergic-blocking agents propranolol and phentolamine, to stimulate or inhibit calorigenesis in various ways. To see whether the effects of these drugs on calorigenesis could be ascribed to effects on the adenylate cyclase (EC 4.6.1.1) - cyclic AMP system, and to try to assess thereby the significance of this system in the regulation of nonshivering thermogenesis (NST), changes in the concentration of plasma cyclic AMP were measured as an index (Broadus, A.E., Hardman, J.G., Kaminsky, N. I., Ball, J. H., Sutherland, E.W., and Liddle, G. W.: 1971. Ann. N.Y. Acad. Sci. 185, 50-60) of changes in tissue levels of cyclic AMP. In CA rats, which have a severalfold greater capacity for NST than WA rats, calorigenic responses to noradrenaline, theophylline, noradrenaline plus theophylline, or phentolamine plus theophylline were as much as four times larger than in WA rats, However, the changes in level of plasma cyclic AMP produced by each of these and other treatments were virtually the same for both groups. It would appear, therefore, that the difference between WA and CA rats in ability to produce heat by NST is not a function of the amplitude of changes in tissue levels of cyclic AMP. Nevertheless, it was also observed, and was particularly striking in CA rats, that when a drug or combination of drugs had a stimulatory, inhibitory, or synergistic effect on calorigenesis, it had a similar effect with respect to elevation of plasma cyclic AMP. Altogether, the results indicate that adenylate cyclase and cyclic AMP are likely to be participants in the regulation of NST in the rat, but that they would be subservient in this regard to whatever factors are responsible for acclimation-related differences in capacity for NST.

Nonshivering thermogenesis in the rat. I. The relation between drug-induced changes in thermogenesis and changes in the concentration of plasma cyclic AMP.

M. Lorraine Frydman

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

Nonshivering thermogenesis in the rat. I. The relation between drug-induced changes in thermogenesis and changes in the concentration of plasma cyclic AMP.