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Am J Physiol Regul Integr Comp Physiol 275: R1399-R1411, 1998;
0363-6119/98 $5.00
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Vol. 275, Issue 5, R1399-R1411, November 1998

INVITED REVIEW
Innervation of mammalian white adipose tissue: implications for the regulation of total body fat

Timothy J. Bartness1,2 and Maryam Bamshad2

1 Departments of Psychology, and of Biology, Neuropsychology and Behavioral Neurosciences, Georgia State University, Atlanta, Georgia 30303; 2 Departments of Psychology, and of Neuropsychology and Behavioral Neurosciences and Neurobiology Programs, Georgia State University, Atlanta, Georgia 30303

    ABSTRACT
Top
Abstract
Introduction
Concluding Remarks
References

We review the extensive physiological and neuroanatomical evidence for the innervation of white adipose tissue (WAT) by the sympathetic nervous system (SNS) as well as what is known about the sensory innervation of this tissue. The SNS innervation of WAT appears to be a part of the general SNS outflow from the central nervous system, consisting of structures and connections throughout the neural axis. The innervation of WAT by the SNS could play a role in the regulation of total body fat in general, most likely plays an important role in regional differences in lipid mobilization specifically, and may have a trophic affect on WAT. The exact nature of the SNS innervation of WAT is not known but it may involve contact with adipocytes and/or their associated vasculature. We hypothesize that the SNS innervation of WAT is an important contributor to the apparent "regulation" of total body fat.

obesity; body weight; lipolysis; norepinephrine; sympathetic nervous system; rats; hamsters; sensory afferents; suprachiasmatic nucleus; paraventricular nucleus; hypothalamus; brain stem; medulla; cellularity

    INTRODUCTION
Top
Abstract
Introduction
Concluding Remarks
References

THE PRIMARY SOURCE of stored energy in mammals is lipid, and white adipose tissue (WAT) is the principal site for its storage. When energy needs cannot be met by circulating fuels or stored carbohydrate, lipid is mobilized from WAT through the process of lipolysis, the breakdown of triglycerides into glycerol and free fatty acids (FFA; Ref. 84). Physiological evidence strongly suggests that the sympathetic nervous system (SNS) is involved in the regulation of lipolysis in addition to the role of several humoral substances [e.g., epinephrine (Epi) from the adrenal medulla, glucagon, or ACTH; Refs. 71, 94, 137]. For example, cold exposure increases WAT norepinephrine (NE) turnover and circulating FFA concentrations in rats, responses that are not blocked by adrenal demedullation (45). These data suggest that cold exposure increases the SNS drive on WAT, thereby promoting the mobilization of lipid stores to meet the enhanced thermogenic requirements of decreased ambient temperature. Despite these and other findings (see below), the significance of the role of the SNS innervation of WAT has been debated for over 100 years (77). This debate largely has continued because there was no convincing neuroanatomical evidence showing that WAT is directly innervated by the SNS (reviewed briefly previously, Refs. 52, 79, 89, 127) until recently (140).

We review several topics in this article concerned with the SNS innervation of WAT. First, we briefly discuss WAT adrenergic receptors and their involvement in lipolysis. Then we reexamine the physiological evidence for the SNS innervation of WAT, including electrophysiological, denervation, and stimulation studies of the nerves innervating this tissue. The neuroanatomical evidence for the SNS innervation of WAT follows. This last section is highlighted by the recent use of a viral transneuronal tract tracer to define the chain of functionally connected neurons that comprise the SNS outflow from brain to WAT. The effects of stimulation or ablation of the brain on lipid mobilization are reviewed next. Attempts are made to interpret the findings of these studies in light of the defined SNS outflow from brain to WAT as revealed by the transneuronal tract tracing method. The sensory innervation of WAT is then addressed. Finally, some potential feedback loops for the regulation of total body fat are postulated that involve the SNS innervation of WAT (motor limb) and sensory nerves/humoral factors (sensory limb).

    ADRENERGIC RECEPTORS CONTROLLING WAT LIPOLYSIS BY THE SNS

One likely reason that the SNS innervation of WAT has been largely overlooked is the brisk and reliable stimulation of lipolysis by catecholamines in vitro, especially Epi (133), suggesting that lipid mobilization may be primarily controlled via blood-borne catecholamines. Lipolysis also could be stimulated via neurally released catecholamines from SNS terminals in WAT however. This latter mode of stimulating lipolysis appears likely for the so-called atypical beta -adrenergic receptor (i.e., the beta 3-receptor), where higher concentrations of catecholamines are required for their activation than is typically found in blood (69).

A thorough review of the adrenergic receptor subtypes involved in the lipolytic response is beyond the scope of this review, but it clearly merits brief discussion here. Four subtypes of adrenergic receptors (adrenoceptors) are involved in the control of lipolysis by catecholamines. These include the beta 1-3 subtypes as well as alpha 2-adrenoceptor (for reviews, see Refs. 67-69). Activation of the three beta -receptor subtypes stimulates lipolysis, but the participation of each subtype in lipolysis varies according to the fat pad, species, gender, age, and degree of obesity (69). In contrast, activation of alpha 2-adrenoceptors inhibits lipolysis (for review, see Ref. 68). The beta 1-3- and the alpha 2-adrenoceptors coexist on the same white adipocytes and share NE and Epi as their physiological agonists, but they differ in their effects on the second messenger adenylylcyclase (i.e., beta -receptor activation stimulates whereas alpha -receptor activation inhibits adenylylcyclase; for review, see Ref. 68). Conventional wisdom suggests that the effectiveness of the catecholamines in stimulating lipolysis depends on the balance between the beta - and alpha 2-adrenoceptors (69, 78). That is, when beta -receptor activation predominates, lipolysis is stimulated and, conversely, when alpha -receptor activation predominates, lipolysis is inhibited (67-69). If lipolysis predominates, then hormone-sensitive lipase is activated, the principal intracellular enzyme responsible for the breakdown of triglycerides into monoacylglycerols (129). This enzyme catalyzes the first two steps of lipolysis (129), whereas monoacylglycerol lipase converts the monoacylglycerols into FFAs and glycerol in the final step (43). According to classic "grind and bind" in vitro receptor assays, the affinity of the adrenoceptors for NE is alpha 2 > beta 1 > beta 2 > beta 3 and for Epi is alpha 2 > beta 2 > beta 1 > beta 3 (69).

    PHYSIOLOGICAL EVIDENCE FOR THE SNS INNERVATION OF WAT

The physiological evidence that supports the role of the SNS innervation of WAT in lipid mobilization comes from the results of three methods of affecting or measuring the activity of these nerves: 1) electrophysiological recording, 2) denervation, and 3) electrical stimulation.

Electrophysiological Evidence Suggests the SNS Innervation of WAT

Although the electrophysiological responses of the interscapular SNS nerves that innervate brown adipose tissue (BAT) have been measured under a variety of conditions (35, 106-108), we are aware of only one study where the electrophysiological activity of WAT nerves was measured (86). Specifically, the firing rate of the presumed SNS nerves innervating epididymal WAT decreases when glucose is administered intravenously in laboratory rats but markedly increases when the same amount of the glucose utilization blocker 2-deoxy-D-glucose (2-DG) is given (Fig. 1). Because 2-DG causes a state of energetic emergency in the brain, it seems likely that the increase in the firing rate of the SNS nerves that innervate WAT originates in one or more of the brain structures involved with the general SNS outflow from the brain (120, 121). It has been shown recently, however, that the glucoprivation caused by 2-DG treatment selectively stimulates the adrenal medulla, rather than the nerves innervating WAT (110), making the interpretation of these data somewhat more difficult.


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  		Fig. 1.   Effect of peripherally administered saline, glucose, and 2-deoxy-D-glucose (2-DG) on efferent sympathetic nerve activity to the epididymal white adipose tissue pad of a laboratory rat. [Borrowed from Prog. Neurobiol. 33, A. Niijima, Nervous regulation of metabolism, p. 135-147, 1989, with permission from Elsevier Science (86)].

Denervation of WAT Suggests a Role of the SNS in Lipid Mobilization

The earliest reports of the effects of WAT denervation on lipid mobilization originated from a clinical observation of Mueller in 1906 (cited in Ref. 77). Mueller noticed that a paraplegic patient of his died in a highly emaciated state, yet had substantial amounts of body fat in the denervated half of his lower torso. This observation prompted Mueller to remove part of the lower spinal cord from a dog. This denervation resulted in more WAT accumulating in the paralyzed legs than in the nonparalyzed legs (77).

A more selective method of denervating WAT than spinal cord disruption is to surgically sever the visible nerves entering fat pads. Because each WAT pad is unilaterally innervated, axotomy of one of a pair of WAT pads can be done, with the contralateral WAT pad serving as a within-animal intact neural control. Note, however, that it is impossible to sever selectively only the SNS innervation of the tissue; thus SNS, sensory, and parasympathetic nerves all are cut, although the latter do not seem to exist (see below). Despite this drawback, surgical denervation of WAT is permanent. A more selective approach than axotomy is chemical denervation of the SNS innervation of WAT. Unlike surgical denervation, however, chemical denervation is not permanent (e.g., Ref. 109).

The effects of WAT surgical sympathectomy originate from the extensive pioneering work of Beznak and Hasch (12). Unilateral surgical denervation of the splanchnic nerves of otherwise untreated cats, rabbits, and rats results in denervated pads that are larger than their contralateral intact pads (41-300, 21-75, and 16-158% increases, respectively). The role of the SNS nerves innervating WAT also was tested during conditions of lipid deposition, such as feeding cats and laboratory rats a high-fat diet (12). High fat diet-fed and unilaterally splanchnicotomized cats, but not rats, had approximately four times the lipid deposition in their denervated WAT pads compared with their intact pads. After brief starvation, however, both species had larger denervated than intact WAT pads (12).

Further support for the SNS innervation of WAT comes from additional experiments where WAT was denervated and then the animals were fasted to stimulate lipid mobilization. For example, denervation of rat retroperitoneal WAT pad followed by a 24- (20), 48- (17, 20), or 72-h (20) fast results in denervated pads that are significantly heavier than their intact contralateral controls (17, 20). Denervation, however, also can decrease blood flow to WAT (17). Decreases in blood flow could account for the denervation-induced decreases in lipolysis because they also could concomitantly reduce the availability of circulating lipolytic substances such as glucagon (71) or adrenal medullary released catecholamines (139). Denervation also could affect lipolysis by blocking the SNS-induced increases in capillary permeability (42, 88). This could result in a reduction in lipid mobilization because increased capillary permeability is needed to allow albumin to leave the vasculature, move into the interstitial space, and transport the liberated FFAs. This resulting FFA buildup could, in turn, inhibit lipolysis (84). Therefore, the SNS denervation of the vasculature could inhibit lipolysis either by decreasing the access of lipolytic factors to the adipocytes or by promoting end product inhibition.

The effects of WAT denervation on lipid mobilization also can occur in non-food-deprived animals. For example, the lipid mobilizing effects of estradiol in ovariectomized laboratory rats are severely blunted in denervated retroperitoneal WAT pads compared with its neurally intact contralateral pads (70).

Collectively, the results of these denervation studies suggest that lipolysis is impaired in denervated tissue. It is not known whether this effect is wholly or partially due to denervation-induced decreases in the SNS control of WAT blood flow/vascular permeability, as opposed to a more direct effect on adipocytes.

Electrical Stimulation of WAT Nerves Promotes Lipid Mobilization

Correll (26) developed an in vitro preparation to measure lipolysis through stimulation of the nerves innervating WAT. Epididymal WAT pads are harvested from laboratory rats with their nerves left intact, placed in a beaker containing physiological saline, and the nerves are electrically stimulated. The resulting changes in the FFA concentrations of the incubation medium are measured and considered an indicator of lipolysis. Electrical stimulation of these nerves markedly and rapidly increases the FFA concentration of the medium. This response is blocked by sympathectomy 4-11 days before harvesting and testing and by adding dibenamine, a beta -adrenergic blocker, to the incubation medium of epididymal WAT before electrical stimulation of its nerve supply. These latter results suggest that SNS nerves are responsible for the electrical stimulation-induced increase in lipolysis (26). Furthermore, the blockade of the electrical stimulation-induced increase in FFA concentration occurs for another adrenergic receptor blocking agent [1-(2',4'-dichlorophenyl)-1-hydroxyl-2-(t-butylamino)], a depletor of catecholamine stores (syrosingopine), and for a NE release blocker (BW-392C60) (132). Finally, the monoamine oxidase inhibitor pargyline exaggerates the lipolytic response to electrical stimulation in this in vitro preparation, as does the addition of theophylline, the phosphodiesterase inhibitor (132). This last finding suggests that endogenously released catecholamines are involved in the electrical stimulation-induced increase in lipolysis in this paradigm (132).

The role of the SNS innervation of WAT also was investigated using the in situ preparation of Oro et al. (90). Briefly, this elegant preparation consists of isolation of the vasculature for the inguinal subcutaneous WAT pad (90) or the fat pad associated with the spleen (83) in dogs. This is possible because the blood supply to these pads consists of a single artery and because blood drainage consists of a single vein for each. Thus perfusion of the pads is easily accomplished in situ (83, 101). In addition, the nerve bundle innervating each fat pad is readily separated from the vascular supply, thereby allowing the attachment of stimulating electrodes to these nerves. Thus substances can be infused into the arterial blood supply to the pad, and the venous effluent can be sampled and/or the nerves innervating the WAT pad can be electrically stimulated (40). Two forms of evidence supporting the SNS innervation of WAT and its role in lipid mobilization come from the use of this preparation. The first evidence supports the in vitro work discussed above. Specifically, electrical stimulation of the nerves innervating the WAT pads increases venous FFA concentrations, suggestive of lipolysis (101). Moreover, the electrical stimulation-induced increases in lipolysis appear to involve beta -receptor activation because this effect is blocked by pretreatment with a beta -adrenergic receptor blocker (101). The second set of findings, although strongly implicating the SNS innervation of WAT, most likely result from modulation of the WAT vasculature. That is, electrical stimulation of the nerves innervating the subcutaneous WAT of dogs in situ causes vasoconstriction that is abolished by alpha -adrenergic receptor blockers (85). In addition, electrical stimulation of the inguinal subcutaneous WAT nerves in situ results in an increase in the capillary filtration coefficient due to increases in the permeability of the capillary membrane (42), an effect that can alter the lipolytic rate, as noted above. Before one dismisses the possibility of nonvascular innervation of WAT, however, histological evidence indicates that both the vascular and nonvascular components of WAT are innervated.

    NEUROANATOMICAL EVIDENCE FOR THE SNS INNERVATION OF WAT

Conventional Histological and Histofluorescence Studies Suggest the SNS Innervation of WAT

The first histological study to demonstrate the presence of nerves in WAT was reported by Dogiel 100 years ago (33) using the stain methylene blue. These findings were confirmed some years later using silver-impregnation methods and revealed both vascular and apparent "direct" innervation of adipocytes (13, 51). These early histological data, although suggestive of innervation per se, do not indicate the neurochemical phenotype of the nerves and therefore do not allow them to be identified as sympathetic.

The advent of the histofluorescence technique (38), however, made it possible to identify the nerves innervating WAT as catecholaminergic. The initial report of catecholaminergic innervation of WAT and BAT by Wirsen (134) suggested only vascular SNS innervation for both tissues. Wirsen subsequently reported (135) delicate fibers making apparent contact with BAT, but not WAT, adipocytes. The vascular-associated catecholaminergic innervation of WAT was confirmed shortly thereafter (2, 29), but later, both vascular and parenchyma catecholaminergic innervation were independently reported (3, 31, 97, 116). In one of the most comprehensive of these early studies (116), the catecholaminergic innervation of mesenteric, epididymal, and subcutaneous WAT pads was shown histofluorescently. Specifically, the most extensive catecholaminergic innervation of the vasculature was observed to encapsulate the arteries and arterioles. In addition, this innervation was most pronounced in the mesenteric and epididymal WAT pads (116). Innervation at the level of the capillaries was best seen in mesenteric and epididymal WAT from fasted rats that were then refed, whereas innervation of the parenchyma was best seen in WAT from rats that were only fasted. The success in observing the catecholaminergic innervation of WAT parenchyma may have occurred because fasting decreased fat cell size, thus making it easier to visualize the parenchymal regions of the tissue. Vascular innervation, including the capillaries, was seen at the electron microscopic level, with only ~2-3% of the adipocytes themselves receiving direct innervation (116).

The most convincing evidence of the vascular and nonvascular catecholaminergic innervation of WAT was gathered by combining the histofluorescence technique with confocal microscopy (97). Unfortunately, these data only appear in a preliminary form. Catecholaminergic neural fluorescence is reported in direct contact with adipocytes from laboratory rat epididymal, perirenal, mesenteric, and inguinal WAT, in addition to making contact with the vasculature. Moreover, mesenteric WAT had the highest, and inguinal WAT the lowest, degree of direct catecholaminergic innervation of adipocytes (97). This ranking is somewhat surprising for the mesenteric WAT because electrical stimulation of the superior mesenteric nerves in dogs does not affect lipolysis (4), although its unusually high basal lipolytic rate might make it difficult to observe an even higher lipolytic rate. It is noteworthy, however, that the most and least densely innervated fat pads (i.e., mesenteric and inguinal, respectively) generally show the highest and lowest rates of NE-stimulated lipolysis in vitro (118).

Use of Fluorescent Tract Tracers Helps to Define the SNS-WAT Connections

We recently took a different approach to determine the catecholaminergic innervation of WAT using fluorescent anterograde and retrograde neuronal tract tracers (140). These experiments were inspired by the finding that the decrease in body fat seen when Siberian hamsters are exposed to short "winterlike" photoperiods is not uniform across WAT pads (10). Specifically, the more internally located WAT pads (i.e., epididymal and retroperitoneal WAT) initially exhibit greater relative degrees of lipid mobilization than the more externally located WAT pads (i.e., inguinal and dorsosubcutaneous WAT; Ref. 10). Therefore, we hypothesized that there was a greater SNS drive on the more internally located, than the more externally located, WAT pads. Moreover, this differential SNS drive on WAT may be one of the mechanisms underlying the differential mobilization of lipid stores in this and other conditions (32, 50, 92). For this to be a physiological reality, however, these pads had to have somewhat separate postganglionic SNS innervation. Therefore, we injected the fluorescent retrograde tract tracer FluoroGold into inguinal or epididymal WAT pads of separate groups of Siberian hamsters to determine directly if differential postganglionic SNS innervation of these WAT pads existed. Although the relative distribution of labeled postganglionic neurons in the sympathetic chain was not completely separate for the two pads, the neurons innervating the epididymal pad had a more rostral pattern of labeling compared with the inguinal pad. Control experiments also were conducted, where the tracer was purposely injected into surrounding muscle, into the vasculature, or into the WAT pads after surgical denervation. In all three tests, there was either no or light labeling in the sympathetic chain. These connections were confirmed by injecting the sympathetic chain with the fluorescent anterograde tract tracer iodocarbocyanine perchlorate (DiI). Rings of fluorescence around each adipocyte in both pads were seen (140). These data provide the first direct neuroanatomical evidence of the innervation of WAT by the postganglionic neurons of the SNS in any species.

The hypothesized greater SNS drive on the more internally located epididymal WAT pads, compared with their more externally located inguinal WAT pads in short day-exposed Siberian hamsters was supported physiologically. Specifically, NE turnover was greater in the epididymal than the inguinal WAT pads after the initial exposure to short days (140). Thus both neuroanatomical and neurochemical support for the notion that WAT has differential SNS innervation and drives was demonstrated. These results do not provide information as to the degree of vascular or nonvascular innervation of WAT nor the location of the divergence of the SNS outflow from the brain to WAT. The results of dozens of studies using electrical or chemical stimulation or lesions of central nervous system (CNS) sites suggest that the origins of the SNS drive on WAT exist centrally and, moreover, operate functionally independent of the control of the adrenal medullary secretion of catecholamines (see below). Therefore, we were interested in defining the CNS circuits connected to the postganglionic innervation of WAT histologically.

    DESCENDING CNS PATHWAYS INNERVATING WAT

Use of a Viral Transneuronal Tract Tracer to Define the Hierarchical Chain of Functionally Connected Neurons From the Brain to WAT

Although the results of many physiological studies suggested that chains of neurons originating in rostral portions of the neuroaxis formed descending polysynaptic pathways that terminated in WAT (see below), no technique was available to define such connections within the same animal. With the use of a viral transneuronal tract tracer, the Bartha's K strain of the pseudorabies virus (PRV), however, the ability to define multisynaptic circuits within the same animal became possible (37). Specifically, some viruses, like the PRV, are taken up into neurons after binding to viral attachment protein molecules located on the surface of neuronal membranes. These protein surface molecules act as "viral receptors." Neurons synapsing on infected cells become exposed to relatively high concentrations of the virus particles that have been exocytosed. The virus particles are then taken up by synaptic contact, and this process continues, causing an infection along the neuronal chain from the periphery to higher CNS sites (58, 119). The infected neurons can be visualized easily using standard immunocytochemical methods. The major advantage of using viruses as transneuronal markers over some of the more traditionally used tracers is their ability to replicate within the neuron and thus act as a self-amplifying cell marker (58, 119).

The utility of this technique to characterize the connections from the brain to a peripheral target tissue, such as WAT, relies on the transfer of the virus by a specific transsynaptic mechanism, rather than by lateral spread to adjacent, but unrelated, neurons or by a nonsynaptic mechanism. This transsynaptic transfer of the virus appears to be the mechanism by which the Bartha's K strain of the PRV spreads under controlled conditions (18, 58, 119). Loewy and associates (54, 59, 60, 74, 111, 120, 121) have championed the use of the PRV for tracing the multisynaptic circuits from peripheral tissues to the brain, as have Card and associates (18, 99). With the use of this technique, the general SNS outflow from the CNS (120) and the specific SNS descending pathways from the more rostral portions of the neuroaxis to the adrenal medulla have been defined for laboratory rats (121).

We adapted the PRV methodology for the determination of the CNS sympathetic outflow to WAT in Siberian hamsters and laboratory rats (5) and more recently in BAT (Bamshad and Bartness, unpublished observations). Briefly, we made injections of PRV into the inguinal and epididymal WAT pads in Siberian hamsters and the inguinal WAT pad in laboratory rats. Despite making injections into a different tissue (WAT) and in a different species (Siberian hamsters), we found a strikingly similar distribution pattern of infected cells to that reported for the injection of the virus into the adrenal medulla and sympathetic ganglia in laboratory rats (120, 121). Retrogradely labeled cells were identified throughout the neural axis, including the spinal cord [intermediolateral (IML) cell group, central autonomic nucleus], the brain stem (nucleus of the solitary tract, C1 and A5 regions, and the rostroventrolateral, rostroventromedial, and caudal raphe nuclei/areas; Fig. 2), and forebrain [hypothalamic arcuate nucleus, dorsal and lateral hypothalamic areas, zona incerta, and paraventricular, suprachiasmatic, and dorsomedial nuclei (PVN, SCN, DMN, respectively); Fig. 3; and nonhypothalamic zona incerta, medial amygdala, medial preoptic area, septum, and bed nucleus of the stria terminalis (5)]. Figure 4 summarizes these findings schematically. Note that despite various manipulations of the ventromedial hypothalamic nuclei (VMH) and consequent alterations in WAT lipolysis and metabolism (reviewed below), no neurons within the VMH became infected. The general patterns of infections for the inguinal and epididymal WAT pads of the Siberian hamsters were not markedly different, nor were the patterns of infection for the inguinal pads between Siberian hamsters and laboratory rats different (5). Therefore, it appears that WAT receives input from CNS cell groups that are part of the general SNS outflow from the brain to the periphery.


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  		Fig. 2.   Microphotograph of neurons labeled in the brain stem at the level of the rostral ventrolateral and rostral ventromedial medulla and caudal raphe nuclei after injections of Bartha's K strain of the pseudorabies virus into the inguinal subcutaneous white adipose tissue pad of a Siberian hamster.


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  		Fig. 3.   Microphotograph of neurons labeled in the brain stem at the level of suprachiasmatic and paraventricular nuclei of the hypothalamus after injections of Bartha's K strain of the pseudorabies virus into the inguinal subcutaneous white adipose tissue pad of a Siberian hamster.


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  		Fig. 4.   Schematic diagram of the sympathetic nervous system outflow from the central nervous system to white adipose tissue based on studies where Bartha's K strain of the pseudorabies virus was injected into the inguinal subcutaneous and epididymal white adipose tissue pads of Siberian hamsters and laboratory rats. BNST, bed nucleus of the stria terminalis; Lat Septum, lateral septum; MPOA, medial preoptic area: SCN, suprachiasmatic nucleus; DMN, dorsal medial nucleus; PVN, paraventricular nucleus of the hypothalamus; C1, C1 epinephrinergic cell group; A5, A5 noradrenergic cell group; NTS, nucleus of the solitary tract; RVLM, rostral ventrolateral medulla; RVMM, rostral ventromedial medulla; Caudal Raphe, caudal raphe nuclear group; IML, intermediolateral cell column of the spinal cord.

CNS Stimulation Studies Designed to Determine the Brain Sites Involved in the Control of Lipid Mobilization

Electrical or chemical stimulation of the CNS has been used to identify the sites in the brain responsible for the mobilization of body fat stores. These studies provide evidence that implicates a handful of brain structures involved in the control of the SNS drive on WAT, with the VMH receiving the most attention. For some of these studies, descending monosynaptic connections of the forebrain (e.g., Refs. 76, 123), midbrain (75), and brain stem (e.g., Ref. 73) to the IML of the spinal cord already were known and this information was used to help explain the effects of lesions or stimulation on lipid mobilization. In many cases, reasonable conclusions were reached, given the somewhat nonselective nature of the electrical stimulation technique.

Electrical stimulation studies. Electrical stimulation of specific hypothalamic sites can result in increases in circulating concentrations of plasma FFAs and/or glycerol in dogs (27, 91), rabbits (27, 66), cats (8), laboratory rats (9, 124), and rhesus monkeys (27) or decreases in the respiratory quotient (RQ) of rats [indicative of the use of lipid fuels (19)]. This central stimulation-induced increase in lipid mobilization shows some neuroanatomical specificity. For example, electrical or chemical (adrenergic) stimulation of the VMH in rats (117, 124), or electrical stimulation of the VMH in rabbits (27, 66), but not the lateral hypothalamus (LH) in either species, increases plasma FFA concentration (124). Electrical stimulation of other brain sites, however, also can result in increases in plasma FFA concentrations, such as the premammillary area in laboratory rats and the zona incerta in dogs (91) and cats (8). This latter finding is interesting in light of the close proximity of the zona incerta to the DMN and our finding that these nuclei are part of the SNS innervation of WAT (5). Therefore, electrical stimulation of the zona incerta might also be stimulating the adjacent DMN and, in that manner, ultimately increasing the SNS drive on WAT and increasing lipolysis. Finally, electrical stimulation-induced decreases in the RQ, indicative of the metabolism of lipid-derived fuel (84), are seen with electrode placements within, but not lateral to, the SCN (19). Note that the SCN is another brain site involved in the SNS outflow to WAT (5).

Electrically stimulated mobilization of metabolic fuels can cause the specific release of lipid or of carbohydrate fuels. Such biochemical specificity suggests functionally separate CNS outflow, at some level, to WAT and the adrenal medulla because the latter does not appear to be involved significantly in the mobilization of lipid stores (see above). For example, electrical stimulation of the premammillary area in rats (8) and the zona incerta in cats (9) increases plasma FFA/glycerol concentrations without triggering concomitant increases in plasma glucose at some sites. Again, because stimulation of some CNS sites can primarily cause increases in plasma FFA concentrations, but not in plasma glucose concentrations (100, 125), little involvement of the adrenal medulla is suggested in these cases. Other studies showed that the electrical stimulation of the VMH results in the mobilization of FFAs. Moreover, this effect seems to be due to activation of the SNS because it is decreased or blocked by spinal cord sectioning below the first cervical vertebrae (27) or by hexamethonium (sympathetic ganglionic blocker) or propranolol (beta -adrenergic blocker) treatment, but not by phentolamine treatment (alpha -adrenergic blocker; Refs. 66, 124). The slight or absent diminution of elevated plasma FFA concentrations in adrenalectomized rabbits receiving electrical stimulation of the VMH (27, 66) or in adrenal demedullated (ADMx) rats after electrical stimulation of this structure (124) also suggests the lack of involvement of the adrenal medulla.

Chemical stimulation studies. Chemical stimulation of the brain through the application of 2-DG or NE centrally also has been used to infer which CNS sites are part of the SNS outflow from brain to WAT. NE applied intracerebroventricularly to laboratory rats produces increases in plasma FFA and glycerol concentrations accompanied by small increases in plasma glucose concentrations (7). 2-DG applied intracerebroventricularly to rabbits produces rapid increases in plasma FFA concentrations accompanied by slowly rising plasma glucose concentrations (93). The results of either of these manipulations appear to be relatively selective for the mobilization of lipid stores. In addition, this lipid mobilization appears to involve the SNS generally, because beta -adrenergic receptor blockers blunt or diminish intracerebroventricular NE-induced mobilization of lipids in laboratory rats (7) and involve the innervation of WAT specifically (93). This latter conclusion is based on the inability of adrenal demedullation to block the lipid mobilizing effects of 2-DG given peripherally to rabbits (93). When NE or Epi is applied to the VMH, plasma FFA, glucose, and insulin concentrations increase in laboratory rats (117). These responses are distinctly different from those elicited by peripheral administration of either substance (117), indicating a central site of action. In addition, 2-DG injected into the preoptic area of laboratory rats also increases plasma FFA concentrations (22). This latter finding is interesting because the medial preoptic area also is involved with the SNS outflow from the brain to WAT (5).

Collectively, these electrical and chemical stimulation data indicate that lipolysis can be selectively triggered by stimulation of several CNS sites and that these lipid mobilization effects are via the SNS innervation of WAT, rather than via adrenal medullary released catecholamines.

Lesion Studies Showing the CNS Structures Involved in the Control of Lipid Mobilization

Another approach used to determine the brain sites controlling lipid mobilization is to observe the effects of the destruction of selective CNS sites on 2-DG-induced lipid mobilization. With the use of this approach it was found that the 2-DG-induced increases in FFAs are blocked by coronal microknife cuts just behind the SCN that produce rostral forebrain deafferentation (125). These cuts also block the increases in lipid mobilization associated with 24-h fasts, forced exercise (swimming), cold exposure, and insulin-induced hypoglycemia (21). Taken together, these results suggest an anterior hypothalamic or rostral forebrain input to the SNS outflow from the brain to WAT that affects lipolysis. Recall that the SCN is part of the SNS outflow to WAT, as revealed by transneuronal labeling using the PRV (5). Maybe the SCN is the origin of this rostral forebrain input to the SNS outflow from the brain to WAT.

This implication of the SCN as a modulator of lipid mobilization via the SNS innervation of WAT perhaps helps to explain the 24-h rhythms of lipolysis/lipogenesis shown by laboratory rats and mice (25, 72), given the role of the SCN in the generation of circadian rhythms and their entrainment by the photocycle (104). Moreover, SCN lesions disrupt the circadian rhythm of NE turnover (i.e., SNS drive) in the adrenal and pineal glands, liver, heart, and kidney (43). Finally, bilateral SCN lesions block the increases in plasma FFA and glucose concentrations and in food intake elicited by intracerebroventricularly administered 2-DG that normally occur during the day only (138; for reviews, see Refs. 80-82). Collectively, it may be that the SCN controls the daily cycles of lipid mobilization by rhythmically varying the SNS drive on WAT (81).

Additional studies also support the central control of peripheral lipid mobilization. Hexamethonium sympathetic ganglionic blockade decreases or blocks the lipid mobilizing effects of intravenous NE (53) or 2-DG in dogs (49). 2-DG-induced lipid mobilization also is inhibited by epidural anesthesia or by destruction of the thoracic spinal cord in dogs and is blocked by C4-T7 spinal cord transections in adrenalectomized dogs (49) or by C7 transections in laboratory rats (98). 2-DG-induced carbohydrate mobilization is blocked by ADMx in neurally intact or hypothalamically deafferentated rats (125), suggesting that the 2-DG-induced increase in plasma glucose concentrations is due to catecholamine secretion from the adrenal medulla (125). Furthermore, ADMx does not block or blunt the 2-DG-induced increase in plasma FFA concentrations in laboratory rats (125) nor does adrenalectomy in dogs (49). In all, these data suggest that the 2-DG-induced increase in FFAs is not due to adrenal medullary NE- or Epi-stimulated lipolysis, thus implicating the SNS innervation of WAT, findings similar to the effects of electrical stimulation.

Central sites for the origins of the SNS innervation of WAT also have been suggested by the effects of brain lesions alone, without central or peripheral chemical stimulation. In general, the effects of brain lesions on the putative SNS control of lipid mobilization are simply opposite the effects of electrical stimulation of these sites discussed above. For example, lesions of the VMH increase body and lipid mass and food intake in laboratory rats (11, 24, 113). Moreover, the ability to mobilize the expanding lipid stores in rats bearing VMH lesions is severely hampered (14, 87, 125). The results of these and other studies of lipolysis implicate a VMH-to-WAT connection via the SNS, at least as assessed by changes in WAT mass. For example, rats with VMH lesions show blunted lipolysis in response to forced exercise (swimming), fasting, cold exposure, and 2-DG injections (87). Furthermore, unilateral denervation of rat retroperitoneal WAT pads or ipsilateral VMH lesions severely impair the fasting-induced mobilization of lipid from this pad compared with its contralateral, neurally intact WAT pad (14). This ability of SNS WAT axotomy to mimic the inhibition of lipolysis after unilateral VMH lesions suggests to some (14, 87) that WAT receives important SNS innervation. Moreover, it was suggested that the VMH serves as a key component in the rostral circuitry mediating lipolysis during fasting and other conditions (14, 87). Finally, VMH lesions in laboratory rats decrease the SNS drive on WAT (128), as indicated by the reductions in NE turnover, and obliterate the normal day/night rhythms of increases in lipolysis and lipogenesis, respectively (95). These latter findings suggest that damage to the output of the SCN may have occurred, most likely through the known SCN-to-PVN-midbrain/brain stem pathways that course around the VMH as they descend caudally (64, 76, 130).

Generally, the results of these lesion studies reflect one of the principal caveats associated with the use of this technique to help define neural circuits: ancillary damage to surrounding structures may prove crucial to the proper interpretation of the effects of the ablations. It may be that the typically large VMH lesions produced to help ensure the complete destruction of this structure contribute to ancillary damage of nearby structures that are involved in the SNS outflow from the brain to WAT. These structures would include the DMN and PVN of the hypothalamus or their efferents, structures that are part of the SNS outflow from the CNS generally (120, 121) and to WAT specifically (5). This purported role of the VMH in SNS-induced lipolysis is reminiscent of the "myth of the VMH" (47) that originally resulted from the misguided emphasis on this structure for the control of body fat and food intake (e.g., Ref. 24). Later, it was shown that the VMH lesion-induced effects on body and lipid mass and food intake were due primarily to the destruction of the descending fibers from the PVN that course just lateral to the VMH (47, 48, 65, 113, 114); although we recognize apparent bona fide differences between the effects of PVN and VMH lesions on adiposity and food intake (44, 126, 131). Therefore, the presumed effects of VMH lesions on WAT mobilization, as well as the effects of stimulation of the VMH on this response, also may be due to involvement of these descending autonomic pathways (5). Although this explanation is appealing, it appears that we still have an incomplete understanding of the descending forebrain pathways involved with the SNS-induced increase in WAT lipid mobilization. For example, unilateral parasagittal knife cuts that transect this critical descending longitudinal pathway from the PVN and other rostral forebrain structures do not result in unilateral sparing of lipid mobilization in the retroperitoneal WAT pads after fasting (61), as do unilateral VMH lesions (14, 87).

Collectively, the physiological, neurochemical, and neuroanatomical evidence for, not only the SNS innervation of WAT, but also an important role of this innervation in the control of lipid mobilization, seems overwhelming.

    PARASYMPATHETIC INNERVATION OF WAT

There is little evidence for the parasympathetic innervation of WAT. Specifically, acetylcholine esterase measured histochemically or biochemically in laboratory rat WAT shows very sparse histochemical evidence and no biochemical evidence of acetylcholine esterase (1, 2). Given that the researchers did not have the benefit of more sensitive, modern day neuroanatomical and biochemical methodologies, the possibility of parasympathetic innervation should not be dismissed out of hand. Recall that the dual innervation of tissues by both branches of the autonomic nervous system is the norm, not the exception (see for example, hair follicles and sweat glands; Refs. 55).

    EVIDENCE FOR THE SENSORY INNERVATION OF WAT

The presence of substance P in WAT (41) was the first clue that this tissue has sensory innervation. Sensory innervation of WAT was first shown neuroanatomically when the anterograde tract tracer true blue labeled cells in the dorsal root ganglia after implantation into the dorsal subcutaneous and inguinal WAT pads in rats (39). These two findings appear to support the sensory innervation of WAT but leave us with many obvious questions to be answered. For example, if sensory innervation of WAT exists, then what is being sensed? One possibility might be that the sensory innervation of WAT serves to inform the CNS of the size of the peripheral lipid stores. This essentially is the putative role of the WAT-derived substance ob protein (leptin; e.g., Ref. 16) and of the role postulated previously for peripheral insulin (e.g., Refs. 63, 112). One possibility of what might be sensed by these sensory afferents is the physical size of the fat pad measured via mechanoceptors associated with the fascial sheathe that covers WAT (103). Another possibility of what might be sensed is lipolytic rate via chemoreceptors. These could monitor FFAs and/or glycerol, the products of triglyceride breakdown, and thus monitor lipolytic rate. FFAs, but not glycerol, can be transported back into the adipocytes and reesterified into triglycerides (34), making their extracellular concentration a relatively poor predictor of lipolytic rate. Thus local concentrations of glycerol, but not FFAs, could serve as a reliable signal for the sensory neurons that might faithfully reflect not only basal lipolysis, but SNS- or hormone-stimulated lipolysis as well.

Regardless of what is being sensed there are at least four possibilities for the role of these WAT sensory nerves in the control of lipid reserves. First, sensory nerves could participate in the feedback control of the vascular perfusion rate and, as discussed above, could alter the access of lipolytic humoral substances to the WAT cells. Second, the sensory nerves could be part of a neural feedback loop that controls lipolytic rate by altering capillary permeability to albumin, thus affecting the feedback inhibition of lipolysis by increases in extracellular FFA concentration. Third, a "long" neural feedback loop might arise from the sensory nerves innervating WAT that could terminate in the brain structures involved in the SNS outflow from the CNS to WAT. Finally, a "short" neural feedback loop might send information about lipolytic rate to the sympathetic ganglia or the IML of the spinal cord to control SNS-mediated mobilization of lipid stores in WAT.

    CONCLUDING REMARKS AND SUMMARY
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Abstract
Introduction
Concluding Remarks
References

We have been intentionally vague about the exact nature of the SNS innervation of WAT in the reviewed literature above. The innervation of WAT could take one, all, or a subset of three forms: 1) innervation of adipocytes by neural processes forming pre- and postsynaptic units, not unlike the motor innervation of skeletal muscle, 2) en passant innervation of adipocytes, with no clear postsynaptic element and a lesser developed presynaptic structure, or 3) innervation of the vasculature of WAT only. Previous studies of WAT using electron microscopy yielded mixed results with some indication of direct or en passant innervation, whereas only vascular innervation is seen in other studies (115, 135). Clearly, additional experimentation that would make the nerve endings more salient at the electron microscopic level appears necessary for a clearer view.

Is the type of SNS innervation of WAT critical for it to have an important physiological role in lipolysis? We think not. All types of innervation could result in enhanced WAT lipolysis as the result of an increased SNS drive on the tissue. Although this may seem straightforward for the first two possibilities, the SNS innervation of only the vasculature requires some explanation beyond that which was cursorily described above. Rosell (102) suggested that SNS neurons innervate the epithelial lining of the vasculature and can affect the SNS-induced increases in lipolysis indirectly. The capillary filtration coefficient increases with electrical stimulation of the nerves innervating the inguinal subcutaneous WAT pad in dogs in situ, due to increases in capillary membrane permeability (42). Thus, although whole organ studies show that SNS stimulation increases peripheral resistance due to constriction of the arterioles in the vascular bed of WAT, the blood pressure within the pads does not change because vascular permeability increases through SNS-induced increases in pore size (42). Such increases may allow large molecules, such as albumin, to penetrate the intracellular space. A carrier, like albumin, is required to transport the FFAs liberated from the adipocytes during lipolysis because they are insoluble in water (84). The ability of albumin to accept the released fatty acids and transport them away from the adipocytes into the vasculature would permit a high rate of lipolysis because the inhibition of lipolysis by the build-up of FFAs would be less likely to occur (102). The notion that vascular tone can affect the rate of lipolysis via removal of glycerol is supported by the microdialysis of laboratory rat WAT with the beta -adrenoceptor agonist isoproterenol (30).

Although the role of the sensory innervation of WAT is poorly understood at best, the adaptive significance of the sensory innervation of WAT monitoring lipolytic rate directly (e.g., monitoring glycerol), or indirectly by altering capillary permeability (102), seems clear. An exaggerated SNS drive on WAT could result in inappropriate increases in the mobilization of lipid stores relative to the energetic needs of the animal, therefore yielding inappropriate decreases in the size of the lipid reserves. This feedback system could be proximal to the pad, occurring at the level of the sympathetic chain or the IML (i.e., short feedback loop), or more distal to the pad, occurring in the brain stem, midbrain, or forebrain structures involved in the SNS outflow from the brain (i.e., long feedback loop). Because of the similarities between the SNS outflow from the CNS to the adrenal medulla (121), heart (stellate ganglia; 59, 60), WAT (5), and BAT (6), as well as the relatively separate innervation of WAT pads by the SNS postganglionic neurons (140), we suggest that the feedback may be more proximal to WAT than distal (i.e., short feedback loop). This short feedback loop seems more plausible than the long feedback loop because, in another system (i.e., the SNS innervation of laboratory rat mesenteric arteries), sensory denervation produced by capsaicin results in enhanced SNS vasoconstriction responses (96).

If the sensory innervation of WAT is not primary in informing the brain of total body fat, then how does the brain receive information regarding adiposity? Two humorally mediated signals have been championed for this function, peripheral insulin (63, 112, 136) and leptin (15, 63). The CNS can respond to either signal appropriately by adjusting the level of food intake so that the desired level of body fat is achieved. Alternatively, or additionally, leptin could interact with the SNS innervation of WAT to affect the degree of SNS neural drive on WAT (i.e., NE turnover rate). The effects of leptin on SNS activity, however, suggest that it increases BAT, but not WAT NE turnover (23). It should be noted, nevertheless, that intravenously administered leptin to laboratory rats stimulates activation of the early-immediate gene product c-fos, an indicator of cellular activation (57), in a variety of CNS structures including the DMN and the PVN (36). Functional connections to WAT (5), as well as to BAT (Bamshad and Bartness, unpublished observations), via the SNS outflow from these two structures have been demonstrated using the viral transneuronal tract tracer PRV. Therefore, leptin could provide the sensory signal for the CNS activation of the SNS outflow to WAT from such structures as the DMN or PVN and thereby alter the mobilization of lipid stores, a hypothesis offered recently (46).

Finally, the SNS innervation of WAT appears to play an important role in fat pad-specific responses associated with lipid mobilization and may, through the differential suppression of the SNS drive on WAT pads, facilitate the differential accumulation of lipid stores as well. In addition, the SNS innervation of WAT may play a role in fat pad cellularity by affecting adipocyte proliferation and/or differentiation. For example, fat cell number is markedly increased after surgical denervation of the retroperitoneal WAT pad in laboratory rats (28), as well as after denervation of the inguinal WAT pad in Siberian hamsters (141). These findings suggest that the SNS normally inhibits the growth of fat pads, not only through changes in fat cell size via alterations in lipolysis, but also through an as yet to be determined mechanism affecting fat cell number. Support for this notion also comes from the inhibition of fat cell proliferation by NE in an in vitro cell culture system (62). In addition, the development of high fat diet-induced obesity is retarded in laboratory rats treated with the beta 3-adrenoceptor agonist CL-316,243 (56). These data make one wonder what the contribution of the denervation-induced increase in fat cell number is to the blockade of food deprivation-induced decreases in WAT pad mass or, for that matter, any other lipid-mobilizing stimulus? Thus the SNS innervation of WAT may be play a vital role in lipolysis, as well as affecting WAT cellularity through a trophic function.

We conclude this review with a quote from the thought-provoking review of the autonomic nervous system innervation of WAT and BAT of over a decade ago by Trayhurn and Ashwell (127, p. 141). "Investigation of the sympathetic activity of WAT, together with the factors influencing the sympathetic system in the tissue in different physiological and pathological conditions, is an important area for further study. Insight into the basis for regional differences in the metabolic activity of WAT may well emerge from such studies."

    ACKNOWLEDGEMENTS

We thank Drs. Michael Stock, Arthur Loewy, Terry Powley, George Wade, Neil Rowland, John deCastro, and Jacqueline Fine for thoughtful conversations; Mary Margaret Mauer for comments on the manuscript; and Dr. Jacqueline Fine for translating the French article (Ref. 20).

    FOOTNOTES

Address reprint requests to T. J. Bartness.

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T. G. Youngstrom and T. J. Bartness
White adipose tissue sympathetic nervous system denervation increases fat pad mass and fat cell number
Am J Physiol Regulatory Integrative Comp Physiol, November 1, 1998; 275(5): R1488 - R1493.
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