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Molecular Endocrinology 18 (9): 2123-2131
Copyright © 2004 by The Endocrine Society

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Learning New Tricks from Old Dogs: ß-Adrenergic Receptors Teach New Lessons on Firing Up Adipose Tissue Metabolism

Sheila Collins, Wenhong Cao and Jacques Robidoux

CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Sheila Collins, Ph.D., CIIT Centers for Health Research, Six Davis Drive, Research Triangle Park, North Carolina 27709. E-mail: scollins{at}ciit.org.


   ABSTRACT
TOP
 ABSTRACT
THE SYMPATHETIC NERVOUS SYSTEM...
 REPERTOIRE OF ßAR...
 SOME UNANSWERED QUESTIONS AND...
 REFERENCES
 
The three ßAR (ß-adrenergic receptor) subtypes (ß1AR, ß2AR, and ß3AR) are members of the large family of G protein-coupled receptors, each of which is coupled to G{alpha}s and increases in intracellular cAMP levels. In white adipose tissues, catecholamine activation of the ßARs leads to the mobilization of stored fatty acids and regulates release of several adipokines, whereas in brown adipose tissue they stimulate the specialized process of adaptive nonshivering thermogenesis. Noteworthy, in most models of obesity the ßAR system is dysfunctional, and its ability to stimulate lipolysis and thermogenesis are both impaired. Nevertheless, selective agonists for the ß3AR, a subtype that is found predominantly in adipocytes, have been able to prevent or reverse obesity and accompanying insulin resistance in animal models. Whether this is a viable therapeutic option for human obesity is much debated with regard to the existence of brown adipocytes in humans or their ability to be recruited. Nevertheless, probing the physiological changes in adrenoceptor function in rodent obesity, as well as the process by which ß3AR agonists promote a thermogenic shift in fuel use, have yielded unexpected new insights into ßAR signaling and adipocyte physiology. These include the recent discovery of an essential role of p38 MAPK in mediating adaptive thermogenesis, as well as the accessory role of the ERK MAPK pathway for the control of lipolysis. Because these metabolic events were traditionally ascribed solely to the cAMP/protein kinase A system, the integration of these signaling mechanisms may pose new therapeutic directions in the quest to counter the obesity epidemic in our midst.


   THE SYMPATHETIC NERVOUS SYSTEM AND ADIPOSE METABOLISM
TOP
 ABSTRACT
 THE SYMPATHETIC NERVOUS SYSTEM...
REPERTOIRE OF ßAR...
 SOME UNANSWERED QUESTIONS AND...
 REFERENCES
 
WHEN NUTRIENTS ARE plentiful, adipocytes both synthesize and take up nonesterified fatty acids, which are converted to triacylglycerol and stored in lipid droplets. The amount stored reflects the cumulative sum over time of the differences between energy intake and energy expenditure (1). On the contrary, net caloric deprivation—whether it occurs in response to extended food scarcity or fasting, sustained intense physical activity, or even during the latter hours of sleep (overnight fasting)—triggers the sympathetic nervous system (SNS) (2). The net efflux of fatty acids from adipose tissue alternates between being maximal after an overnight fast or during a bout of exercise to being minimal or nonexistent 60–120 min after a meal to manage minute-to-minute metabolic demands (3, 4).

Both white adipose tissue (WAT) and brown adipose tissue (BAT) are innervated by the SNS (5, 6, 7, 8). Sympathetic innervation is more abundant in BAT than in WAT, and thus neural-derived norepinephrine is presumed to play a greater role in BAT, particularly during cold exposure and in response to leptin treatment (9, 10, 11). Nevertheless, in WAT there can be a significant degree of norepinephrine turnover in the immediate vicinity of the nerve terminals, particularly during cold exposure (12). Anatomical and physiologic details on the role of the SNS in the control of lipolysis have been extensively investigated and reviewed recently (13, 14, 15).

The recipients of these catecholamine signals are the {alpha}-adrenergic receptors (ARs) and the ßARs. They are members of the large family of G protein-coupled receptors that are integral membrane proteins of the plasma membrane, which couple to members of the heterotrimeric G proteins to ultimately convey an intracellular signal. In the case of the ßARs, they activate adenylyl cyclase and the cAMP-dependent protein kinase (PKA). Whereas our focus in this review is on the ßARs and their ability to fire up adipocyte fuel mobilization and thermogenesis, catecholamines can also be antilipolytic per se in white fat through the {alpha}2ARs and their inhibition of cAMP production. The relative proportions of these AR subtypes vary between species, fat depots, and metabolic status (16). Whereas rodent species possess abundant levels of the adipocyte-specific ß3AR and lesser amounts of the two other subtypes, the reverse is generally the case in humans, although there is clearly a need to examine intraabdominal depots in normal-weight humans more carefully. Thus, the relative amounts of the ßAR and {alpha}2AR can contribute to the efficacy of catecholamines for triglyceride hydrolysis, and there is evidence from both animals and humans for increases in the overall adipocyte {alpha}2AR/ßAR ratio in obesity (17).

The SNS activation of lipolysis and thermogenesis through the ßARs is a well-established phenomenon from many years of detailed pharmacologic and physiologic study. There are three subtypes of ßARs (ß1AR, ß2AR, and ß3AR) (18, 19, 20), all of which are expressed in white and brown adipocytes (21, 22, 23, 24). They are all coupled to activation of adenylyl cyclase and PKA but, as will be explored here, other signaling mechanisms exist downstream of PKA or in some cases independent of PKA, that are important players in the control of adipocyte metabolism. More recently, genetic engineering studies eliminating all ßARs placed an extra nail in the coffin of proof that the ßARs mediate the sympathetic control of adipose metabolism (25, 26). Interestingly, Jimenez et al. (26) also showed in their study that the lipolytic response to fasting was still relatively intact. This situation is not unlike what has been observed in several independent reports on hormone-sensitive lipase (HSL)-null mice, in which lipolysis during fasting was in fact moderately elevated as compared with wild-type mice (27, 28, 29, 30). We can speculate that this ßAR- and HSL-independent lipolysis may involve a new lipase that has a greater PKA-independent component, revealing an aspect of regulation to be further explored.

In the white adipocyte, PKA ultimately leads to the phosphorylation of HSL and perilipin A (31, 32, 33, 34, 35). It has been shown that phosphorylation of HSL by PKA increases the catalytic activity of the purified enzyme only modestly as opposed to the large increases in lipolysis seen in vivo (discussed in Ref. 36). The exact mechanism is not understood but seems to involve the concerted phosphorylation of HSL, perilipin, and perhaps other lipid droplet-associated molecules. Because of the tight association of perilipins with the lipid droplet in the basal state (37, 38, 39), it is thought that phosphorylation of these components facilitates their intermolecular association thus favoring HSL access to triglycerides (35, 40, 41). However, any number of other targets and intermediary molecules could be involved that are as yet unidentified. This point is underscored by the recent identification of other lipid droplet binding proteins such as S3–12 (42), caveolin-1 (43), and proteomic approaches in progress reveal a large number of unidentified molecules. In the case of the brown adipocyte, a comprehensive review of BAT thermogenesis has recently appeared (44), and the reader is referred to it. Our focus on brown adipocytes in this review will address the signaling mechanisms involved in ßAR-induced uncoupling protein gene expression and the molecular events in expansion of mitochondrial uncoupling capacity.


   REPERTOIRE OF ßAR SIGNALING MECHANISMS IN ADIPOCYTES AND CONSEQUENCES FOR LIPOLYSIS AND THERMOGENESIS
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 ABSTRACT
 THE SYMPATHETIC NERVOUS SYSTEM...
 REPERTOIRE OF ßAR...
SOME UNANSWERED QUESTIONS AND...
 REFERENCES
 
The consensus model of catecholaminergic control of adipocyte metabolism through ßAR stimulation of cAMP and PKA is under pressure to be modified by the recent discovery that two MAPK cascades, ERK1/2 and p38, have emerged as players in the biology of both white and brown adipocytes. By way of background, the ability to activate the ERK pathway by ßARs, particularly the ß2AR, in different cell types is now well established (45). For ß2AR, the pathway is pertussis toxin-sensitive (i.e. involvement of Gi) and perturbed by inhibitors of PKA because of a requirement for PKA phosphorylation of the receptor to facilitate interaction with Gi (46). Our interest in this pathway arose out of attempts to understand the molecular basis for the powerful and specific ability of ß3AR agonists to stimulate thermogenesis and brown adipocyte recruitment in model systems (reviewed in Ref. 47). As a result, we discovered that ß3AR indeed couples interchangeably to both Gs and Gi to activate PKA as well as ERK in both white and brown adipocytes (48). But unlike previous descriptions of this mechanism for a G protein-coupled receptor, the ß3AR does not require receptor phosphorylation. Instead it involves the recruitment of c-Src kinases to intracellular domains of the ß3AR that contain conserved proline motifs (49) and is independent of both Gs and PKA (Fig. 1Go). A report suggesting a role for PKA in the Src-dependent activation of ERK by ß3AR in brown adipocytes is discrepant with our studies (50) and may be due to their use of higher concentrations of H89 and the less selective ß3AR agonist BRL-37344, which can also activate the ß2AR to a modest extent (23, 24). For the activation of p38 MAPK, it is dependent on Gs and PKA because it is downstream of ß-agonist increases in cAMP levels and PKA activity (49, 51). Therefore, in both white and brown adipocytes the ERK and p38 MAPK cascades appear to be independent of each other (49) and activated in response to catecholamines by different mechanisms. From these observations, it was necessary to next determine what physiological effect, if any, these MAPK pathways control in adipocytes before delving into mechanistic biochemistry.



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  		Fig. 1. Mechanisms of WAT Lipolysis Stimulation by ßARs

In the basal state (A), nonphosphorylated HSL is in the cytosol probably bound to some cytosolic acceptors such as lipotransin, and nonphosphorylated perilipin tightly is bound to the lipid droplet. HSLs do not have free access to the droplet, so most of the basal lipolysis is attributed to an yet nonidentified additional lipase. When catecholamines interact with the ßARs, the later can alternatively couple to both Gs and Gi. The former lead to the sequential stimulation of adenylyl cyclase and PKA, which is bound via its regulatory subunits to juxtamembranous anchor proteins called AKAPs. The catalytic subunits of PKA can than, have access to both HSL, which is phosphorylated at two serine residues in the regulatory region (Ser-659 and Ser-660), and perilipin, which is phosphorylated at six serine residues, three in the regulatory region (Ser-81, Ser-222, and Ser-276) and three in the carboxyterminal portion (Ser-433, Ser-494, and Ser-517). On the other hand, Gi activation leads to EGF receptor transactivation and activation of the ERK pathway. The ERK pathway, in turn, can also lead to the phosphorylation of HSL (Ser-600) and probably perilipin.

 
ERK1/2 MAPK and Lipolysis
By different experimental approaches, ß3AR activation of the ERK pathway generally appears to account for between 15 and 25% of total lipolysis (Ref. 52 ; and Robidoux, J., W. Cao, M. Cyr, A. V. Medvedev, K. W. Daniel, S. C. Souza, A. S. Greenberg, C. Holm, and S. Collins, manuscript submitted). Our pharmacologic analyses suggest that at low catecholamine concentrations essentially all lipolysis is activated by PKA, whereas the ERK1/2 pathway may be most significant at higher concentrations of norepinephrine (Robidoux, J., W. Cao, M. Cyr, A. V. Medvedev, K. W. Daniel, S. C. Souza, A. S. Greenberg, C. Holm, and S. Collins, manuscript submitted). In addition, because of the prevalence of ß2AR as well as ß1AR in adipocytes in all species, particularly human, and their ability to also activate the ERK pathway it is reasonable to speculate that there is a generic role for ERK in lipolysis, even though it is likely to be a lesser contributor than PKA.

p38 MAPK and Thermogenesis
The functional consequences of p38 MAPK activation in white adipocytes are as yet unknown, but in brown adipocytes it is now clear that the transcriptional activation of the uncoupling protein (UCP) 1 gene depends upon a series of events that include stimulation of the p38{alpha} MAPK downstream of cAMP/PKA irrespective of the ßAR subtype, and the recruitment and p38-dependent activation of PGC-1{alpha} [peroxisome proliferator-activated receptor (PPAR) {gamma} coactivator-1] (54) (Fig. 2Go); a promiscuous coactivator capable of interacting with a number of different nuclear receptors (55). PGC-1{alpha} is readily detected in brown fat but only very weakly in WAT, and substantial evidence supports an important role for PGC-1{alpha} in regulating mitochondriogenesis and oxidative metabolism (55, 56, 57). From our recent work (54), it now also appears that the increased expression of PGC-1{alpha} that is observed as a consequence of ßAR-mediated cAMP stimulation in the brown adipocyte in vivo or in cell culture models in vitro involves p38 MAPK (Fig. 3Go). Figure 4Go provides a working model for our understanding of the regulation of UCP1 by the SNS. The initial acute cAMP-dependent increase in thermogenesis involves PKA activation of lipolysis to activate the existing UCP1 protein in the mitochondria (reviewed in Ref. 58). This is followed by a cAMP-dependent induction of UCP1 gene transcription that occurs by a concerted surge of signals. The p38 MAPK phosphorylation of ATF-2 as well as PGC-1{alpha} allows the CRE and PPAR elements of the UCP1 enhancer to be occupied. Together with the induction of the transactivation of the PGC-1{alpha} gene itself by p38-activated ATF-2, these events permit a sustained thermogenic response by increasing PGC-1{alpha}-dependent mitochondriogenesis and greater amounts of UCP1 protein to reside within those mitochondria. All of these new findings require additional studies to establish the metabolic ramifications of these simultaneous signaling cascades emanating from ßARs and, importantly, there must be follow-up studies using primary adipose tissue samples from humans to assess the importance of these pathways in humans. However it is intriguing that the most important regions of the UCP1 promoter are highly conserved between rodents and humans (Fig. 5Go).



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  		Fig. 2. Mechanisms of BAT Thermogenesis Stimulation by ßARs

Under the basal state, the PKA and p38 MAPK pathways are quiescent. When catecholamines interact with the ßARs, they lead to the sequential stimulation of adenylyl cyclase and PKA, which in turn activates a specific protein kinase cascade culminating on the activation of p38{alpha} and thus activation of a subset of transcription factor including ATF2. A second phase response ensues, in which newly transcribed PGC-1 transactivates members of the PPAR family and therefore UCP1 expression.

 


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  		Fig. 3. cAMP-Dependent PGC-1{alpha} Transcription in Brown Adipocytes Is Regulated by p38 MAPK

Left, Effect of PKA and p38 MAPK inhibitors on the activity of the PGC-1{alpha} promoter in HIB-1B cells transfected with PGC-1{alpha}-CAT. Right, ATF-2 binds to the promoter region of PGC-1{alpha} containing the CRE. [Adapted with permission from W. Cao, J. Robidoux, P. Puigserver, A. V. Medvedev, X. Bai, L. M. Floering, B. M. Spiegelman, and S. Collins: Mol Cell Biol 24:3057–3067 (54 ). © American Society for Microbiology.]

 


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  		Fig. 4. Cartoon of Coordinate Control of UCP1 and PGC-1{alpha} Gene Transcription by PKA and p38 MAPK in Brown Adipocytes

Please refer to details in text and legend to Fig. 2Go and Ref. 54 .

 


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  		Fig. 5. Alignment of the Enhancer Region of the UCP1 Promoter from Mouse, Rat, and Human

The nomenclature of candidate transcription factor binding sites is that of Kozak (77 ) and Graves (78 ).

 

   SOME UNANSWERED QUESTIONS AND CONUNDRUMS
TOP
 ABSTRACT
 THE SYMPATHETIC NERVOUS SYSTEM...
 REPERTOIRE OF ßAR...
 SOME UNANSWERED QUESTIONS AND...
REFERENCES
 
The notion that one could develop therapeutic agents to stimulate thermogenesis as antiobesity and antidiabetic treatments arose out the discovery of ß-adrenergic compounds that could increase oxygen consumption and cause selective loss of white adipose stores in the extremely obese mutant ob/ob mouse (59). This continues to be discussed, albeit without much success. The background of these efforts have been previously reviewed (47). However, to this day the most puzzling but immensely intriguing feature is the de novo appearance of brown adipocytes within typical white adipose depots, suggesting a close interplay between these two adipocyte species. The source of these brown adipocytes is unknown. They may arise from proliferation, but no evidence in support of this can be found (60). There is currently discussion in the field that small pockets of dedifferentiated brown adipocytes from the neonatal period may be present in white adipose depots, expressing very low amounts of ß3AR, but which might be triggered to redifferentiate (61). However, as discussed above, although this response to catecholamines clearly has a predominant cAMP component, the targets of these pathways are still unknown. At least one target appears to be PGC-1{alpha}, whereas other intriguing reports of novel regulators of brown fat thermogenesis include the retinoblastoma protein (62) and CIDE-A (63).

This is all very interesting from a laboratory exercise, but humans, except at birth, do not have homogenous BAT depots as do rodents. Nevertheless, one can observe variable quantities of brown adipocytes dispersed through several of the typical WAT depots in humans (64, 65). Moreover, from studies in mouse strains with differential susceptibility to dietary obesity (66) evidence is emerging that perhaps brown adipocytes within these WAT depots may be more important for the antiobesity effect of thermogenic stimuli (67) such as ß3AR agonists (68). Therefore, certain fat depots appear more able to change between the white and brown adipocyte phenotype in an age or environment-dependent manner (61, 64, 69, 70, 71, 72, 73). Now under debate in the field is the possibility of transdifferentiation between the WAT and BAT phenotype (74), and even a form of white adipocyte that could have high oxidative capacity not necessarily dependent upon UCP1 (75, 76). These are concepts that seem to fly in the face of traditional developmental biology but, if true, changes the way we think about cell type specificity in general and may provide some much-needed new angles to target thermogenesis for weight loss.


   FOOTNOTES
 
Abbreviations: AR, Adrenergic receptor; BAT, brown adipose tissue; HSL, hormone-sensitive lipase; PGC-1{alpha}, PPAR{gamma} coactivator-1; PKA, cAMP-dependent protein kinase; PPAR, peroxisome proliferator-activated receptor; SNS, sympathetic nervous system; UCP, uncoupling protein; WAT, white adipose tissue.

Received for publication May 7, 2004. Accepted for publication July 1, 2004.


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 SOME UNANSWERED QUESTIONS AND...
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