Brown Adipo Tissue:
Function and Physiological Significance
BARBARA CANNON AND JAN NEDERGAARD
The Wenner-Gren Institute,The Arrhenius Laboratories F3,Stockholm University,Stockholm,Sweden
I.A Mammalian Prerogative:Brown Adipo Tissue 278II.Norepinephrine Controls the Thermogenic Process工商银行面试
280A.Norepinephrine signaling through 3-receptors leads to thermogenesis 280B.Thermogenesis is due to activation of UCP1through lipolysis 283C.The ␣2-adrenergic pathway inhibits thermogenesis
288D.The ␣1-adrenergic pathway and the cell membrane events 289III.The Life of the Brown Adipocyte Is Under Adrenergic Control
290A.In brown preadipocytes,norepinephrine promotes proliferation
小公鸡292B.In mature brown adipocytes,norepinephrine promotes differentiation 292C.Norepinephrine directly regulates the expression of the UCP1gene 293D.Norepinephrine is an apoptosis inhibitor in brown adipocytes 294IV.How Significant Is Brown Adipo Tissue?
295A.Parameters of activation and recruitment
295B.How to establish brown adipo tissue involvement 297V.Thermoregulatory Thermogenesis
298A.In acute cold,thermogenesis results from shivering
298B.Classical nonshivering thermogenesis is entirely brown fat dependent
299C.Cold acclimation-recruited,norepinephrine-induced thermogenesis is entirely
brown fat dependent
301D.Postnatal thermogenesis
303E.Fever,hyperpyrexia,and anapyrexia (stress,anesthesia,thyroid thermogenesis,exerci)305F.Hibernation and arousal
311G.The central regulation of thermoregulatory thermogenesis and the innervation
of brown adipo tissue
313VI.Metaboloregulatory Thermogenesis
316A.The acute thermal effects of eating
316B.Recruiting diets (obesity,leptin,cachexia)
318C.Influence of x hormones on brown adipo tissue 324D.Central regulation of metaboloregulatory thermogenesis 325VII.Uptakes and Clearances
328A.Lipid clearance and brown adipo tissue
328B.Is brown adipo tissue an important organ for gluco clearance?
329C.During nonshivering thermogenesis,brown adipo tissue is the major oxygen-consuming organ
in the body
331VIII.Brown Adipo Tissue as a Secretory Organ
331A.Autocrine 331B.Paracrine 333C.Endocrine
334IX.Significance of Brown Adipo Tissue for Humans and Other Mammals
335A.Brown adipo tissue and humans
335B.Benefits of nonshivering thermogenesis
337
Cannon,Barbara,and Jan Nedergaard.Brown Adipo Tissue:Function and Physiological Significance.Physiol Rev 84:277–359,2004;10.1152/physrev.00015.2003.—The function of brown adipo tissue is to transfer energy from food into heat;physiologically,both the heat produced and the resulting decrea in metabolic efficiency can be of significance.Both the acute activity of the ,the heat production,and the recruitment process in the tissue (that results in a higher thermogenic capacity)are under the control of norepinephrine relead from sympathetic nerves.In thermoregulatory thermogenesis,brown adipo tissue is esntial for classical nonshivering thermogen-Physiol Rev
84:277–359,2004;10.1152/physrev.00015.2003.
支持存储卡esis(this phenomenon does not exist in the abnce of functional brown adipo tissue),as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis.Heat production from brown adipo tissue is acti-vated whenever the organism is in need of extra ,postnatally,during entry into a febrile state,and during arousal from hibernation,and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus.Feeding as such also results in activation of brown adipo tissue;a ries of diets,apparently all characterized by being low in protein,result in a leptin-dependent recruitment of the tissue;this metaboloregulatory thermogenesis is also under hypothalamic control.When the tissue is active,high amounts of lipids and gluco are combusted in the tissue.The development of brown adipo tissue with its characteristic protein,uncoupling protein-1(UCP1),was probably determinative for the evolutionary success of mammals,as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.
I.A MAMMALIAN PREROGATIVE:
BROWN ADIPOSE TISSUE
In popular and in formal definitions of the animal group to which we belong,the mammals,our ability to feed our young in a practical way is the one characteristic normally advanced.However,it is not this characteristic alone that has given us an evolutionary advantage.Nota-bly,a unique organ,brown adipo tissue,exists in mam-mals.Brown adipo tissue is probably the outcome of a single evolutionary development,occurring very early during the evolution of mammals.Although impossible to prove,good arguments can be forwarded that this ,the acquisition of brown adipo tissue with its new protein,uncoupling protein-1(UCP1,thermoge-nin),may have been the one development that gave us as mammals our evolutionary ,to survive and especially to be active during periods of nocturnal or hibernal cold,to survive the cold stress of birth,and probably also by promoting our survival on diets low in esntial macronutrients,especially protein.The func-tional significance of this unique mammalian organ is the subject of this review.
In contrast to other mammalian organs,brown adi-po tissue is still scientifically a rather new organ.Al-though described in certain mammals since1551(244), the realization that brown adipo tissue is found in all mammals has occurred within the last century.That heat production is one of the functions of brown adipo tissue has only been formulated for40years(751),and the involvement of the tissue in or even its full responsibility for diver types of metabolic ineffi,as a pos-sible
antiobesity organ)has only been discusd for some 20years(680).The identification of UCP1as the mito-chondrial protein responsible for the unique function of brown adipo tissue is of a similar short age(19,311).
The prent review is a further contribution to a ries of reviews and books on nonshivering thermogen-esis and brown adipo tissue(332,379,446,575,754, 816).Very detailed reviews of brown adipo tissue func-tion in general,especially in connection with metabolic control,were compiled in the late1980s(328,329,331), and we will not here replicate the efforts.
Brown adipo tissue morphology has been particu-larly elegantly prented recently(133),but the impacts of the scientific developments of the last decade have not been synthesized into a comprehensive analysis of brown adipo tissue function.The last decade has brought us an understanding of the background of genetically obe phenotypes,the identification of a family of mitochondrial carrier proteins(659)more similar to UCP1than to any other protein(raising questions concerning the unique-ness of brown fat-derived thermogenesis and metabolic inefficiency)and,as new experimental tools,the develop-ment of mice strains deficient in brown adipo tissue (462)or in UCP1(200),which in their turn have allowed for the demonstration of the esntiality of UCP1for thermogenesis in the brown adipocytes(491)and for nonshivering thermogenesis in the intact animal(
260,262, 565).We have thus in the prent review concentrated on issues developing during the last decade.With now more than5,000articles dealing to some extent with brown adipo tissue as such,there is no possibility to be com-prehensive,nor is it possible to encompass general bio-logical concepts;we attempt only to reference obrva-tions made specifically in brown adipo tissue.We have nevertheless attempted to be conclusive,in the light of available evidence,often to the exclusion of occasional contradictory evidence(which,perhaps,may ultimately become the more correct interpretation);we con-quently apologize for misinterpretations,oversights,and omissions.
Certain types of experiments on brown adipo tis-sue are often performed on particular species of animals, e.g.,mice,rats,and Syrian and Djungarian hamsters.We have tried to avoid qualifying each statement as to spe-cies,strain,or other condition investigated,provided we have not considered this type of qualification esntial. We thus discuss a generic brown adipo tissue.We con-centrate especially on the functional significance of brown fat-derived ,to what extent are alterations in metabolism and metabolic efficiency,ob-rved under a broad variety of physiological conditions, explainable through brown adipo tissue thermogenic activity(e cts.V and VI).However,to be able to do this,we initially describe the thermogenic mechanism in the single heat-producing unit,the brown adipocyte,and
278BARBARA CANNON AND JAN NEDERGAARD
how the functional capacity of brown adipo tissue may be ,the recruitment process)(e cts. II–IV).We also discuss the extent to which brown adipo
tissue may play a systemically important role in other respects than thermogenesis,by releasing or extracting substances to or from the circulation(e cts.VII and VIII),and wefinalize with a short comment(e ct.IX)on brown adipo tissue function in the mammalian species that attracts much of our interest:humans.
To facilitate the more detailed discussion that will follow,a general overview of brown adipo tissue func-tion within the mammalian organism can be en in Fig-ure1A.Although the thermogenic unit is the brown adi-pocyte,placed in the center of Figure1,it is evident from thefigure that even within the tissue,the brown adipocyte cannot work in isolation:its activity is controlled by the nervefibers reaching each cell,and the brown adipocyte is dependent on adequate delivery of oxygen and sub-strate(lipids)through the capillaries surrounding each cell(212);the delivery of its product,heat,to the organ-ism is equally dependent on the heated blood leaving the tissue.Thus,although the brown adipocytes themlves constitute the main volume of the tissue,the mature brown adipocytes are pro
bably in minority among the cells in the tissue(241),with the largest number of cells being the endothelial cells of the capillaries,and the interstitial cells and preadipocytes that,under conditions of incread thermogenic demand,will divide and differ-entiate to form new brown adipocytes.In such recruit-ment phas,not only the number of brown adipocytes but also the capillaries and the nerve terminals have to expand in a coordinated way to fulfil the new demands.
The study of the physiological signficance of the tissue would have been much simpler if brown adipo tissue was only found in one place in the body.How-ever,as summarized in Figure1B,brown adipo tissue is found in defined but disperd areas in the body,and brown adipocytes may be identified in clusters even within white adipo tissue depots,to a varying degree in different animals or strains of animals.Therefore, the metabolic significance of the tissue in different physiological conditions is still not fully established, but as will be evidenced in the prent review,it is an organ with unique
functions.
FIG.1.A:an overview of the acute control of
火车票购买时间
brown adipo tissue activity.Information on body
temperature,feeding status,and body energy re-
rves is coordinated in an area in the brain that is
probably the ventromedial hypothalamic nucleus
(VMN).When there is reason to increa the rate of
food combustion(decrea metabolic efficiency)or
increa the rate of heat production,a signal is
transmitted via the sympathetic nervous system to
the individual brown adipocytes.The relead
transmitter,norepinephrine(NE),initiates triglycer-
ide breakdown in the brown adipocytes,primarily
via
3
-adrenergic receptors.The intracellular signal
is transmitted via cAMP and protein kina A,lead-
ing to the relea from triglycerides(TG)of fatty
acids(FFA)that are both the acute substrate for
thermogenesis and(in some form)the regulators of
the activity of uncoupling protein-1(UCP1,ther-
mogenin).Combustion of the fatty acids in the re-
spiratory chain(RC)leads to extrusion of Hϩ,and
UCP1thus allows for mitochondrial combustion of
substrates,uncoupled from the production of ATP,
by functionally being(the equivalent of)a Hϩtrans-
porter.The outcome is that an incread fraction of
the food and the oxygen available in the blood is
taken up by the tissue and combusted therein,lead-
ing to an incread heat production.The participa-
tion of brown adipo tissue in total energy metab-
olism is,at least in smaller mammals,very substan-
tial;at“normal”ambient temperatures,nearly one-
纪公庙half of their energy metabolism may be related to
brown adipo tissue activity,and in small mam-
mals living in cold environments,the predominant
energy utilizer is brown adipo tissue.The capacity
of the tissue for the metabolism of the animals
alters thus as an effect of environmental conditions:
it atrophies when not needed and it becomes re-
cruited when a chronic,high demand is encoun-
tered.B:brown adipo tissue distribution in the
body.
BROWN ADIPOSE TISSUE279
II.NOREPINEPHRINE CONTROLS THE
THERMOGENIC PROCESS
The minimal functional thermogenic unit of brown adipo tissue is the brown adipocyte itlf.For an un-derstanding of brown adipo tissue function,and espe-cially for an understanding of how different physiological conditions may lead to an alteration(recruitment or atro-phy)in the total thermogenic capacity of the tissue,an understanding of the factors that influence the acute ac-tivity of the brown adipocyte,as well as its birth,devel-opment,and death,is necessarily of importance.Classical knowledge concerning the brown adipocyte was re-viewed in Reference567.
Among the factors that influence the brown adipo-cyte,norepinephrine is both the most important and the most well-studied.This effector is most significant phys-iologically,not only for the acute thermogenic process but also for the control of cell proliferation,advanced cell differentiation,and apoptosis.We thereforefirst review adrenergic signaling in brown adipocytes,leading to-wards regulation of the acute thermogenic process.Ad-renergic effects on cell proliferation,differentiation,and apoptosis are discusd in ction III.
A.Norepinephrine Signaling Through
3
-Receptors Leads to Thermogenesis
1.
3
-Adrenoceptors in mature brown adipocytes
In mature brown adipocytes,norepinephrine inter-acts with all three types of adrenergic receptors:,␣2, and␣1;the receptor types are associated with activa-tion of different signaling pathways in the brown adipo-cytes,as will be detailed below.The most significant and the most studied pathway is the pathway for-adrenergic stimulation of thermogenesis(Fig.2).
Of the three subtypes of-adrenergic receptors,the 3-adrenoceptor is the most significant in mature brown adipocytes from rodents.1-Adrenoceptors are also ex-presd in mature brown adipocytes,but they are not coupled to any significant extent to signaling process in the cells;they are,however,coupled to cAMP produc-tion in brown preadipocytes(76)(e ct.III A),which means that in membrane preparations from total brown adipo tissue,both receptor subtyp
es will be functional (126).2-Adrenoceptors are not expresd in the brown adipocytes themlves(46),but they are expresd in the tissue(651,652)and can be obrved as binding sites in membrane preparations from brown adipo tissue(438, 676).The2-adrenoceptors are probably predominantly localized to the vascular system.
The extent to which the3-adrenoceptor mediates the physiological effects of norepinephrine is routinely examined by comparing the effects of norepinephrine stimulation with tho of a“specific”3-agonist.The3-agonists most commonly ud are BRL-37344(25)(which, however,is only a lective,at higher concentrations it also stimulates2-receptors), CGP-12177(516)(which is an antagonist on1/2-recep-tors),and CL-316243(336)(which must be considered prently as the most lective3-agonist available).It is generally assumed that thermogenesis stimulated by one of the agents(especially CL-316243)in intact animals is indicative of brown adipo tissue thermogenesis,primar-ily becau3-receptors are practically only found in white and brown adipo tissue,and becau the total thermogenic capacity of white adipo tissue is suppos-edly so low that it can be neglected in this context[but this assumption has been challenged(275a)].
The existence of a fourth-adrenoreceptor,the4-receptor,has sometimes been discusd(234,391)
,also in brown adipo tissue(626).One of the properties of this receptor should be that it is stimulated by CGP-12177 (it is thus difficult to differentiate from the3-receptor in normal brown adipocytes).Such a“4-effect”has some-times been ascribed to an atypical activation by CGP-12177of1-receptors in a certain conformation(rather unexpectedly,as CGP-12177is a high-affinity antagonist on the receptors)(275,408).There is thus no gene for this“4-receptor,”and the phenomenon is still not fully clarified.
In addition to being characterized by specific stimu-lation by“specific”3-agonists,3-adrenoceptors are also characterized by a very low affinity for classical
-adren-FIG.2.The3-and␣2-adrenergic signaling pathways in mature brown adipocytes.NE,norepinephrine;G
s
,stimulatory G protein;G
i
, inhibitory G protein(dashed lines with solid circles denote inhibition); AC,adenylyl cycla;PKA,protein kina A;CREB,CRE-binding pro-tein;CRE,cAMP respon element;ICER,inducible cAMP early repres-sor(it is the resulting protein that inhibits the stimulatory effect of phosphorylated CREB on its own transcription and on that of certain other proteins).
280BARBARA CANNON AND JAN NEDERGAARD
ergic antagonists,such as propranolol[with a pA
2ofϳ9
on1/2-receptors andϳ6on,about3 orders of magnitude lower affinity(25,900)].To eliminate 3-stimulation in vivo,very high concentrations of pro-pranolol must therefore be ud(at leastՆ10mg/kg body
女人生日祝福语wt).Unfortunately,no well-recognized high-affinity lec-
日清日结tive3-antagonist is prently available;SR59230A has been suggested(585),but the efficacy of this ligand has been criticized.Thus simple questions concerning the significance of the3-pathway cannot be answered sim-ply,by experimentally inhibiting this pathway lectively.
2.
3
-Adrenoceptors do not posss properties esntial for brown adipo tissue function
The distinct localization of3-receptors to brown and white adipo tissue has led to suggestions that the re-ceptors as such may have functional properties necessary or at least advantageous for(brown)adipo tissue func-tion.This does not,however,em to be the ca.
In this respect,it is noteworthy that the guinea pig lacks identifiable,functional3-receptors in brown adi-po tissue(33),but its brown adipo tissue is nonethe-less fully functional(80,338,456).Similarly,brown adi-pocytes prepared from animals in which the3-gene has been ablated are fully functional,except that in the cells, it is the1-adrenoceptor that mediates the-respon(139, 408,596).The ability of brown adipocytes from3-ablated animals to respond to norepinephrine via1-receptors does not indicate that1-receptors are normally responsible for stimulation of thermogenesis;rather,there is an induced expression of1-adrenoceptors in the animals(781). [The term compensatory is often ud for such a situa-tion,but this is easily interpreted as implying some nearly conscious act on the part of the cell;however,the in-crea in1-adrenoceptor expression is probably coinci-dental,as expression of the1-gene is under positive adrenergic control(46)and is thus lf-inducing under conditions of incread sympathetic tone,which would be expected to occur when insufficient heat is produced due to the abnce of3-receptors.]
The3-receptors distinguish themlves from the1/2-receptors by lacking most of the amino acid residues that are normally thought to be involved in receptor de-nsitization(199,545).It can easily be argued that it would be advantageous for brown adipocytes to posss receptors that were not easily densitized(becau ther-mogenesis often has to proceed for very prolonged peri-ods).It
could therefore be assumed that cells with1-receptors would densitize more rapidly than3-ex-pressing wild-type cells,although there is no published evidence for this.In this context,it is also notable that, although the3-receptor may not be easily experimentally densitized,the3-expression level(mRNA)is dramati-cally downregulated(at least transiently)during continu-ous adrenergic stimulation(47,276,398),and this could
also result in functional densitization.
女人心计It is sometimes stated that3-receptors are less n-sitive to norepinephrine than are1-receptors.Thus it has been claimed that at low levels of sympathetic stimula-tion,it would be the1-adrenoceptors that would be activated(32,233,421).There is,however,no unequivo-cal evidence for this,neither in transfected systems(in which3-receptors have affinities intermediate between 1-and2-receptors,Ref.797),nor functionally in brown adipocytes[the functional EC
50
for cAMP formation by norepinephrine in preadipocytes(where the1-receptor is dominant)is not lower than it is in mature brown adipocytes(76)].[There is,however,a lower nsitivity of the3-receptor than the1-receptor for the pharmacolog-ical-agonist isoprenaline(isoproterenol)(596).]A
t low norepinephrine concentrations,the thermogenic re-spon is more nsitive to a given do of propranolol than it is at high norepinephrine concentrations(32),but this is an inherent feature of interaction between agonists and antagonists and does not indicate a shift from1-receptors at low to3-receptors at high norepinephrine.
It has also been suggested that3-receptors could
have a dual coupling to the transducing G proteins(to G
i as well as to G
s
,e below),but as the splice variant expresd in mou brown adipo tissue does not have this property(363a),this would em not to be a general phenomenon in native brown adipocytes.
Thus,at prent,there is no evidence that the pres-ence of3-receptors(as compared with1/2-receptors) on brown adipocytes and their coupling to thermogenesis is anything other than coincidental,and the3-receptor apparently does not confer to the brown adipocytes any demonstrated physiological advantage.However,the prence of the3-receptors predominantly(alt
hough not exclusively)on white and brown adipocytes means that the receptors are potentially convenient targets for drugs against obesity,even bearing in mind the lower functional significance of the receptors in human than rodent adipo tissue.
3.Only G
s
proteins couple to thermogenesis
-Adrenergic receptors normally couple to G pro-
teins of the G
s
subtype.This coupling has been indirectly demonstrated in brown adipo tissue,since norepineph-rine infusion enhances the ability of cholera toxin to
ADP-ribosylate the G
s
protein(274)and cholera toxin can mimic the effects of-stimulation(479).G s proteins exist
in G
s␣L and G s␣S forms in brown adipocytes as in other tissues;during differentiation from brown preadipocytes to mature brown adipocytes,the G
s␣S variant increas, without any change in G
s␣L(72)and without any func-tional change being obrved.
Bad mainly on experiments with ectopically ex-
BROWN ADIPOSE TISSUE281
