Neural innervation of white adipose tissue and the control of lipolysis

Highlights

• Principal stimulator of lipolysis in mammals is the sympathetic nervous system (SNS).

• White adipose tissue (WAT) has sensory innervation of spinal origin.

• Alterations in SNS drive affects adipocyte proliferation in addition to lipolysis.

• WAT does not appear to possess parasympathetic innervation.

• Insulin and adenosine inhibit SNS-induced lipolysis.

Abstract

White adipose tissue (WAT) is innervated by the sympathetic nervous system (SNS) and its activation is necessary for lipolysis. WAT parasympathetic innervation is not supported. Fully-executed SNS–norepinephrine (NE)-mediated WAT lipolysis is dependent on β-adrenoceptor stimulation ultimately hinging on hormone sensitive lipase and perilipin A phosphorylation. WAT sympathetic drive is appropriately measured electrophysiologically and neurochemically (NE turnover) in non-human animals and this drive is fat pad-specific preventing generalizations among WAT depots and non-WAT organs. Leptin-triggered SNS-mediated lipolysis is weakly supported, whereas insulin or adenosine inhibition of SNS/NE-mediated lipolysis is strongly supported. In addition to lipolysis control, increases or decreases in WAT SNS drive/NE inhibit and stimulate white adipocyte proliferation, respectively. WAT sensory nerves are of spinal-origin and sensitive to local leptin and increases in sympathetic drive, the latter implicating lipolysis. Transsynaptic viral tract tracers revealed WAT central sympathetic and sensory circuits including SNS-sensory feedback loops that may control lipolysis.

Introduction

Despite abundant data to the contrary, many textbooks, reviews and research papers continue to assert that adrenal medullary catecholamines, especially epinephrine (EPI), is the primary stimulator of lipolysis by white adipose tissue (WAT). This dogma belies the conclusive data showing that the removal of the sole source of circulating EPI by bilateral adrenal demedullation (ADMEDx) does not block lipolysis (e.g., Nishizawa and Bray, 1978, Takahashi and Shimazu, 1981). By contrast, the sympathetic nervous system (SNS) innervation of WAT is sufficient and necessary for the initiation of WAT lipolysis and performs a commanding function in the adjustment of lipid energy stores. Thus, this review will focus on the support for the direct SNS innervation of WAT as the principal initiator of lipolysis in mammals, including, of course, humans, as well as the role of the SNS in another WAT functions – fat cell proliferation. The typical counterpart to the SNS is the parasympathetic nervous system (PSNS) and despite some suggestion to the contrary (e.g., Kreier et al., 2002), the PSNS innervation of WAT and a function to oppose lipolysis is unfounded or trivial at best (Berthoud et al., 2007, Giordano et al., 2006, Giordano et al., 2007) as will be briefly discussed below. We also will describe the sensory innervation of WAT and its potential functions in the control of lipid metabolism. Finally, we will not describe in detail the SNS innervation of brown adipose tissue (BAT) and its role in energy balance, except its role to act in concert, or separately, from the SNS innervation of WAT in response to several challenges to energy balance because we have recently reviewed the literature on this topic (for review see: Bartness et al., 2010). Because we also have reviewed the SNS innervation of WAT recently and across the years (e.g., Bartness et al., 1993, Bartness et al., 2010, Bartness et al., 2005, Bartness and Song, 2007a, Bartness and Song, 2007b), we will make every attempt not to repeat this information, although some reiteration is necessary. Instead, we will add to this growing body of knowledge embellishing previous topics with new findings, suggest new areas of research to deepen our understanding of its role in lipolysis, and to speculate about the various mysteries of this area that remain to be solved.

Before delving into the heart of the review, we feel it would be helpful to indicate the location of the WAT depots we will be discussing primarily in rodent model research, as well as to compare and contrast them with WAT depots in humans. Tchkonia et al. (2013) nicely demonstrate the location of WAT depots in rodents and humans (Fig. 1). Although there are some similarities in WAT depots [e.g., mesenteric WAT (MWAT), perirenal WAT, retroperitoneal WAT (RWAT) – the latter not clearly shown; Fig. 1], there also are striking differences including the absence of omental WAT in rodents, the presence of perigonadal WAT in rodents [epididymal WAT (EWAT) or parametrial WAT (PWAT)] but their absence in humans, and differences in the extent of the subcutaneous WAT with restriction of these depots around the haunches in rodents [inguinal WAT (IWAT) and dorsosubcutaneous WAT (DWAT)], but underlying most of the skin in humans, and finally the absence of leg WAT in rodents. We feel these differences are not trivial distinctions and that conclusions based on rodent models, whether involving functional differences between visceral and subcutaneous WAT as well as individual WAT depots, should be made with more caution that historically or currently is the practice.

Our interest in the study of the SNS innervation of WAT was driven by our initial focus on the naturally-occurring decrease in the body fat of Siberian hamsters (Phodopus sungorus) triggered by changes in daylength. During the long days (LDs) of summer, their impressive obesity (e.g., ∼50% of body mass as body fat Bartness et al., 1989, Wade and Bartness, 1984) is at its peak and is reversed to a more moderate level of adiposity (∼20% of body mass as body fat) in the short days (SDs) of winter in the field naturally (Weiner, 1987). Fortunately, these naturally-occurring changes in lipid mass can be mimicked in the laboratory by changing only the photoperiod from LDs to SDs, while holding all other environmental factors constant such as temperature and food availability (Wade and Bartness, 1984; for review see: Bartness et al., 2002, Bartness and Wade, 1985). This is because for Siberian hamsters, and many other species exhibiting seasonal changes in adiposity and reproductive status, the daylength (photoperiod) cue is translated into a neuroendocrine signal via the duration of the nocturnal secretion of melatonin (MEL) from the pineal gland that occurs in direct proportion to the length of the dark period (for review see: Bartness and Goldman, 1989, Bartness et al., 1993, Goldman, 2001) thereby stimulating the MEL_1a receptor (a.k.a. MT₁-R) subtype that mediates photoperiodic responses (e.g., Roca et al., 1996). Because MEL does not affect lipolysis in vivo even at ‘industrial strength’ doses (Ng and Wong, 1986), an intermediary must exist. Even though there was nearly 100 years of suggestive, indirect evidence for the SNS innervation of WAT and its role in lipid mobilization (lipolysis), we fell into the trap of most researchers of the 1980s studying lipolysis and focused on circulating factors – in the case of Siberian hamsters, those that changed with changes in the daylength that also had been implicated in altering lipolysis [e.g., epinephrine (EPI), glucocorticoids, prolactin, thyroid hormones, gonadal steroids, insulin; for review see: Bartness et al., 2002]. None of these factors could account for the photoperiod-induced reversal of obesity by Siberian hamsters; therefore, there appeared to be a non-circulating factor initiating WAT lipolysis – perhaps a neural one. In addition, another factor favoring a ‘neural hypothesis’ was that in our initial and follow-up studies of the photoperiodic reversal of seasonal obesity, the intra-abdominal WAT pads (EWAT, RWAT) had the greatest degree of lipid mobilization, with the IWAT pad showing a lesser and later degree of lipid mobilization (Bartness, 1995, Bartness, 1996, Bartness et al., 1989, Wade and Bartness, 1984), a feat that could be accomplished by a circulating factor if its receptor number/affinity/signaling cascade varied accordingly among the WAT depots, or more simply by differential SNS drive to pads via its innervation and the release of norepinephrine (NE), the principal sympathetic nerve neurotransmitter. Indeed, in vitro lipolysis increases in isolated white adipocytes incubated with physiological concentrations of NE (e.g., Fain and Garcija-Sainz, 1983, Pecquery et al., 1983).

As noted in brief above, historically, but also unfortunately presently, adrenal medullary EPI often is ascribed as the primary initiator of WAT lipolysis. Perhaps this is due to the profound lipolysis engendered by application of physiological concentrations of the monoamine to WAT fragments ex vivo or isolated adipocytes in vitro (e.g., Bukowiecki et al., 1980, Leboeuf et al., 1959, Prigge and Grande, 1971, Rochon and Bukowiecki, 1990, Rosak and Hittelman, 1977, White and Engel, 1958, Wool et al., 1954). The role of adrenal medullary EPI for in vivo lipolysis has been discredited, however, because adrenal demedullation (ADMEDx), which removes the sole source of circulating EPI, does not block fasting-, exercise-, electrical stimulation of the hypothalamus- or glucoprivation-induced lipid mobilization in laboratory rats and mice or lipid mobilization in SD-exposed Siberian hamsters (Demas and Bartness, 2001, Kumon et al., 1976, Nishizawa and Bray, 1978, Takahashi and Shimazu, 1981, Teixeira et al., 1973).

Glucagon has long been implicated in mediating WAT lipolysis (Gjedsted et al., 2007, Lefebvre et al., 1973, Lefebvre, 1975, Lefebvre and Luyckx, 1969, Luyckx et al., 1975, Vaughan and Steinberg, 1963), but its effects on lipolysis are independent of CNS action because WAT SNS denervation does not block glucagon-induced glycerol release (an index of lipolysis), although it does decrease free fatty acid (FFA) release (Lefebvre et al., 1973). The latter effect is not due to a blockade of the effects of glucagon on lipolysis, rather it is attributed to re-esterification (Lefebvre et al., 1973). Indeed, exogenously administered i.v. glucagon that results in physiological concentrations of the hormone does not stimulate lipolysis in vivo as assessed by intra-WAT microdialysis (Gravholt et al., 2001).