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Brown adipose tissue (BAT) has been known to be present in all mammals including man. While this fact has been known for sometime, the function of this tissue in thermogenesis (heat production) Physiologist 4: 113–113, 1961.   with its implications for obesity has only been recognised in recent times. Nature. 1979 Sep 6;281(5726):31-5.  While man has always considered efficiency as a positive feature in most settings, metabolic efficiency of an extreme nature in the adipose tissue could result in lower levels of thermogenesis, resulting in a state of positive energy balance. Metabolic inefficiency would probably be welcome in the obese patient who could afford to lose calories in every  possible way. While shivering is an effective response to producing body heat with resultant loss of calories, a tendency of the body to produce a shivering response in the midst of calorie excess-if it was present- would have resulted in obese patients shivering their way to our clinics! Brown adipose tissue is involved in non-shivering thermogenesis, Biol Rev Camb Philos Soc. 1973 Feb;48(1):85-132.  as evidenced by thermographic imaging  showing higher body surface temperature over BAT depots. Acta Paediatr Scand. 1972 Jan;61(1):42-8. and the observation that BAT is activated on chronic cold exposure.  Can J Physiol Pharmacol. 1979 Mar;57(3):257-70.  This non shivering thermogenesis (does not include basal metabolism which  in strict terms is also non-shivering thermogenesis)  in the brown adipose tissue is controlled by a centrally controlled pathway in the hypothalamus. It would be tempting and simplistic to think that lean people probably increase their non-shivering thermogenesis in response to calorie intake although this has not been borne out in studies. Metabolism. 1986 Feb;35(2):166-75.
Brown adipose tissue is present in humans as in other mammals although it is present in significant quantities in neonatal life  Proc Nutr Soc. 1989 Jul;48(2):243-56.   with the likely function of offering a survival advantage in the newborn. The ability of neonates to produce heat by shivering is restricted to a degree by their cardiovascular and muscular capacity and hence non shivering thermogenesis from brown fat is crucial as is well evident from the need for incubators for premature infants with lower amounts of brown fat. Brown fat is thought to have mainly two functions, one of thermoregulatory thermogenesispredominantly concerned with heat regulation of the body, and another of ensuring wastage of excess calories ingested (metaboloregulatory thermogenesis). The amount of brown adipose tissue decreases in adults partly as a function of increased heat production from basal metabolism and partly due to the ability of the excess weight to produce an insulation to a degree coupled with artificial insulation offered by clothing.  While adult adipose tissue has been traditionally thought to have no brown adipose tissue, Clin Sci (Lond). 1985 Sep;69(3):343-8.   it is presently being increasingly understood that islands of brown adipose sites may exist within white adipose tissue, with up regulation in pathological states of increased adrenergic activity.  Int J Obes Relat Metab Disord. 1992 May;16(5):383-90. as demonstrated by the presence and up regulation of UCP-1, (Un-Coupling Protein) the specific marker of brown adipose tissue.
Mechanism of Thermogenesis

So how does brown adipose tissue function as a thermogenic organ? Futile cycles resulting in wasting of ATP with its conversion to ADP and consequently substrate oxidation or oxygen consumption in mitochondria could be a potential mechanism, but the demonstration of low  ATP synthase capacity in brown fat mitochondria J Cell Biol. 1967 Jul;34(1):293-310.    makes ATP consumption as an unlikely mechanism. It was then recognised that in the absence of UCP-1 (uncoupling protein), noradrenaline or fatty acids could not induce thermogenesis in brown adipocytes. J Biol Chem. 2000 Aug 18;275(33):25073-81.   The uncoupling protein as implied by its name, uncouples the oxidation from ATP formation, such that ATP formation is not crucial to facilitate substrate oxidation.

Fatty acids produced from lipolysis of triglycerides are bound to the high amounts of fatty acid binding proteins (FABP) in the cytosol of the brown adipose tissue. They are then transported to the mitochondria via the carnitine shuttle where they are β oxidised with energy release. In contrast to mitochondria elsewhere in the body, the mitochondria in  brown adipose tissue are prevented from conserving energy at this stage but instead produce thermogenesis, (and high respiratory rate) by the presence of high levels of UCP-1 in the BAT mitochondria. UCP1, also called thermogenin or GDP-binding protein, Eur J Biochem. 1978 Jan 16;82(2):515-21  is a member of the mitochondrial carrier protein family.  UCP1 is almost exclusively expressed in the brown adipose tissue, with reports of extra adipose expression being attributed to methodological problems of non specificity and cross reactivity. Expression in white adipose tissue of UCP1 is attributable to probably functional brown adipose tissue islets in the white adipose tissue. Physiol. Rev. 84: 277-359, 2004.  Although closely related proteins UCP2 and UCP 3 have been described, they do not seem to be involved nor crucial in noradrenaline-mediated thermogenesis as evidenced by studies in models of UCP2 ablated  Nat Genet. 2000 Dec;26(4):435-9. and UCP3 ablated mice. J Biol Chem.2000 May 26;275(21):16258-66   Also the level of these proteins (UCP2 and UCP3)  is not high in brown adipose tissue J Biol Chem. 2001 Mar 23;276(12):8705-12.    despite high levels of their mRNA expression in BAT.  The role of these proteins in brown adipose tissue and elsewhere remains to be clarified.


UCP-1 expression in brown adipose tissue increases up to ten fold with chronic exposure to cold. Am J Physiol. 1994 Oct;267(4 Pt 2):R999-1007.   UCP-1 knock out mice continue to maintain shivering to the same extent as prior to the knock out  FASEB J. 2001 Sep;15(11):2048-50.    suggesting that in the absence of the contribution from BAT, the only source of thermogenesis is that from shivering-induced heat production by muscles, without an increase in basal metabolism (which is contributed to mainly by the muscles). Noradrenaline can still elicit thermogenesis in these UCP-1 knock out mice through its adrenergic effects on muscles, Biochim Biophys Acta. 2001 Mar 1;1504(1):82-106  clearly independent of UCP-1, but with a possible mediation through UCP2? It is more likely that this thermogenesis is not mediated through uncoupling but merely ATP synthesis followed by energy wasting by increasing muscle metabolism. UCP-1 knock out mice do not become obese despite the inability for non-shivering thermogenesis.
Regulators of Thermogenesis

The functional activity of brown adipose tissue is determined by the acute effects of noradrenaline on thermogenesis in BAT, the degree of differentiation of BAT as well as the total number of brown adipocytes, the latter being determined by rates of proliferation and apoptosis, in conjunction with other factors including density of mitochondria, UCP 1 levels and alterations in vascular supply to brown adipose tissue. As is easily understandable, effects on thermogenesis by acute activation of the sympathetic system and thus activation of the brown adipose tissue can happen within seconds, while proliferation and differentiation takes longer time (days to weeks) following chronic sympathetic stimulation.
Noradrenaline acts on brown pre adipocytes to increase their proliferation through a β-1 adrenoceptor mediated effect J Biol Chem. 1992 Jan 25;267(3):2006-13.  with a reduction in PPARγ2 levels. Noradrenaline also facilitates differentiation of mature brown adipocytes through a cAMP dependent process, as well as an increase in the number of mitochondria. Am J Physiol.1987 Dec;253(6 Pt 1):C889-94   Noradrenaline which produces thermogenesis also induces lipolysis with glycerol or fatty acid release from brown adipose tissue, through its activating effect on the hormone sensitive lipase in the adipose tissue which is crucial to produce lipolysis as demonstrated in HSL deficient mice.  Obes Res. 2001 Feb;9(2):119-28.   This lipolytic action of noradrenaline is mediated through β 3 adrenoceptors and is essential to produce the fuel for thermogenesis as described below. In contrast, alpha 1 adrenoceptors in brown adipocytes are also stimulated by noradrenaline and seem to produce inhibition of thermogenesis through inhibition of adenyl cyclase with decrease in cAMP levels, J Biol Chem. 1999 Dec 31;274(53):37770-80   thus offering a concomitant counter regulatory mechanism that could result in regulation of thermogenesis at various times although the factors influencing preferential action on the alpha or β receptors of noradrenaline have not  been defined yet. Yet it should be noted that effects of alpha 1 adrenergic stimulation on thermogenesis is small. Eur J Pharmacol. 1983 Sep 30;93(3-4):183-93.
Adrenaline also produces a UCP1 dependent thermogenesis in brown adipose tissue,   J Physiol. 1969 Nov;205(2):393-403. although slightly lower than that produced by similar amounts of noradrenaline. Eur J Pharmacol. 1983 Sep 30;93(3-4):183-93.  Activation of thermogenesis in brown adipose tissue requires high pharmacological levels of adrenaline, while lower physiological doses of adrenaline is thought to produce thermogenesis through a hormonal mechanism independent of BAT resulting from an increase of metabolism by about 10%. Clin Auton Res. 1994 Jun;4(3):131-6.   The primary physiological relevance of this hormonal effect though may not be adaptive thermogenesis itself.

Fatty acids, like noradrenaline, can also induce a thermogenic process in the adipose tissue, J Biol Chem. 1968 Dec 10;243(23):6077-83.   fully mediated via the UCP-1 protein.  J Biol Chem. 2000 Aug 18;275(33):25073-81   In fact, lipolysis and increase in fatty acids is always accompanied by thermogenesis. Also, thermogenesis in brown adipose tissue always requires lipolysis.

Thyroid hormones increases basal metabolic rate with increased thermogenesis. A central effect of thyrotoxicosis to produce hyperpyrexia is also recognised. Ann N Y Acad Sci. 1997 Mar 15;813:712-7.   Thyroid hormones do not seem to induce thermogenesis in brown adipose tissue, although one would have expected the increased adrenergic state to contribute to such a mechanism of action. On the other hand, one would also expect the increased thermogenesis through increased metabolism to produce a negative feedback with resultant atrophy of brown adipose tissue in thyrotoxic patients, which seems to be likely. Pflugers Arch. 1976 Apr 6;362(3):241-6 ;  Am J Physiol. 1981 Sep;241(3):C134-9;
The human scene

A significant adaptive non-shivering thermogenesis in response to cold exposure in humans has not been demonstrable with noradrenaline administration. J Appl Physiol. 1970 Jul;29(1):6-9.;   J Appl Physiol. 1963 Nov;18:1209-12. 

Morbidly obese subjects show a significantly lower age- and gender-adjusted UCP mRNA expression in the intraperitoneal adipose tissue, while UCP mRNA abundance in extra peritoneal adipose tissue was similar in the obese and nonobese. J Lipid Res. 1997 Oct;38(10):2125-33. These could at least partly account for reduced energy expenditure in obesity, but its contribution to the pathogenesis of obesity remains to be clarified. Induction of UCP remains a potential therapeutic option for obesity through induction of thermogenesis, but such an attempt would have to be tissue specific without producing uncoupling of oxidation in sites other than adipose tissue (immune cells, cardiocytes and brain which have UCP2) which would be deleterious. Hence targeting UCP would require molecules to be delivered specifically to the intracellular or mitochondrial compartment which remains impossible at this point.
Difficulties with experimental interpretation

Systemic injection of noradrenaline produce thermogenesis Am J Physiol. 1994 Jun;266(6 Pt 1):E877-84. but probably does not represent a physiological scenario due to the diffuse and simultaneous stimulation of all adrenergic receptors in the body produced by the systemic injection.  On a similar note the high doses of propranolol needed to inhibit the beta 3 adrenergic receptors in the adipose tissue produces generalised beta adrenergic inhibition thus making it difficult for beta 3 specific effects to be inferred.

Studies involving acute cold stress result in recruiting shivering thermogenesis in addition to non shivering thermogenesis and it would be difficult to tease out the contribution of the latter alone to heat production.

Absence of perilipin -(the protein that normally covers the triglyceride droplets in the cell protecting it from hormone sensitive lipase action) -in artificial triglyceride emulsions makes assessment of lipolytic activity induced in vivo by exogenous infusion of triglyceride infusions difficult.

In vivo, brown adipose tissue is in different stages of differentiation in contrast to cell cultures where all cells are in similar stages of differentiation. Hence the consistent effects elicited by intervention in vitro is easier to interpret but probably cannot be easily translated or correlated with the varied effects produced in vivo by cells in varying stages of differentiation.Adipose Tissue Protocols, edited by G Ailhaud. Totowa, NJ: Humana, 2001, p. 213–224.