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Keywords:

  • sympathetic;
  • parasympathetic;
  • leptin;
  • insulin resistance;
  • lipolysis

Abstract

  1. Top of page
  2. Abstract
  3. WAT: a traditional endocrine gland
  4. WAT: a metabolic organ
  5. WAT: getting nervous
  6. Conclusion
  7. References

Neuroendocrine research has altered the traditional perspective of white adipose tissue (WAT) as a passive store of triglycerides. In addition to fatty acids, WAT produces many hormones and can therefore be designated as a traditional endocrine gland actively participating in the integrative physiology of fuel and energy metabolism, eating behaviour and the regulation of hormone secretion and sensitivity. WAT is controlled by humoral factors, para- and intracrine factors and by neural regulation. Sympathetic nerve fibres innervate WAT and stimulate lipolysis, leading to the release of glycerol and free fatty acids. In addition, recent research in rats has clearly shown a functional parasympathetic innervation of WAT. There appears to be a distinct somatotopy within the parasympathetic nuclei: separate sets of autonomic neurones in the brain stem innervate either the visceral or the subcutaneous fat compartment. We therefore propose that the central nervous system (CNS) plays a major role in the hitherto unexplained regulation of body fat distribution. Parasympathectomy induces insulin resistance with respect to glucose and fatty acid uptake in the innervated fat depot and has selective effects on local hormone synthesis. Thus, the CNS is involved not only in the regulation of hormone production by WAT, but also in its hormone sensitivity. The developments in this research area are likely to increase our insights in the pathogenesis of metabolic disorders such as hypertriglyceridemia, diabetes mellitus type 2 and lipodystrophy syndromes.

In the first half of the 20th century, white adipose tissue (WAT) was viewed mainly as an isolated tissue protecting the organism from heat loss and as a passive store of energy. In general, adiposity was seen as the net result of excess substrate. However, this perspective of WAT function is an oversimplification. WAT is capable of producing a large number of hormones in addition to fatty acids. Many of these hormones act at distant organs, especially on the central nervous system (CNS), thereby affecting eating behaviour, energy balance and hormone sensitivity. WAT is controlled by the interaction of humoral factors (hormones, substrates), local factors (e.g. fat cell size, para- and intracrine mechanisms) and neural input from the autonomic nervous system. The CNS has both sympathetic and parasympathetic neural connections with fat depots, which alter many aspects of WAT function. In this review, we focus on the interaction between the neural input and the metabolic WAT functions and discuss the possible implications for the pathophysiology of complex metabolic diseases.

WAT: a traditional endocrine gland

  1. Top of page
  2. Abstract
  3. WAT: a traditional endocrine gland
  4. WAT: a metabolic organ
  5. WAT: getting nervous
  6. Conclusion
  7. References

The identification of leptin in 1994 (1) marked the beginning of the understanding of WAT as an endocrine tissue. Initially, leptin was viewed as an antiobesity hormone. This was based on the finding that total deficiency of leptin, or its receptor, leads to marked hyperphagia and morbid obesity both in mice and in humans. Moreover, peripheral or intracerebroventricular (i.c.v.) administration of recombinant leptin decreased fat mass through increased energy expenditure and less food intake in rodents. Finally, the administration of recombinant leptin to a child with congenital leptin deficiency was reported to decrease fat mass (2).

However, the putative role of leptin as an antiobesity hormone contrasted with the inability of high serum concentrations of leptin to reduce weight in most obese individuals. Therefore, it was suggested that the physiological role of leptin is to act as a switch between fed and fasted states (3, 4). The fall in serum leptin during fasting in mice triggers a dramatic decrease in the secretion of growth hormone, thyroid and reproductive hormones, and an increased activity of the hypothalamus-pituitary-adrenal axis. In rats, the suppressive effect of decreased serum leptin during starvation on the hypothalamus-pituitary-thyroid (HPT) axis was shown to be mediated via neuropeptidergic pathways originating in the hypothalamic arcuate nucleus where the leptin receptor is expressed. These monosynaptic pathways to the paraventricular nucleus (Fig. 1a) suppress thyrotropin-releasing hormone expression and thereby the HPT axis (5, 6).

image

Figure 1. Neural and endocrine connections between the central nervous system (CNS) and white adipose tissue (WAT). (a) Schematic representation of the WAT–CNS circuit. The paraventricular nucleus (PVN) receives input from a number of hypothalamic nuclei such as the suprachiasmatic nucleus (SCN), which is the circadian clock of the brain, and the arcuate nucleus (ARC), where leptin receptors are expressed. The PVN sends autonomic projections to the dorsal motor nucleus of the vagus (DMV), where parasympathetic motor neurones innervating WAT are located. These pathways can be visualized by retrograde trans-synaptic tracing from WAT after selective sympathetic denervation. In addition, the PVN projects to the intermediolateral column (IML), representing the source of sympathetic WAT innervation. The autonomic innervation of WAT has profound effects on insulin sensitivity, thereby affecting free fatty acid and glycerol production, and on gene expression of adipose tissue hormones such as resistin and leptin. These metabolic and endocrine signals are sensed in the CNS (e.g. in the Arc). The scheme represents a feedback loop from the hypothalamus to adipose tissue (neural pathway) and back (endocrine pathway). (b) Transneuronal retrograde tracing of WAT–CNS circuit. Pseudorabies virus (PRV) was injected into retroperitoneal fat in rats before (a and b) and after (c and d) sympathetic denervation of adipose tissue. Transverse sections of the spinal cord at Th 7 (a and c) and the brain stem at the level of the obex (b and d) show spinal cord and brain stem neurones projecting to WAT. In (a) and (b) (intact rats) the tracer is is present in sympathetic fibers in the spinal cord (intermediolateral column, IML) and in sympathetic and parasympathetic (DMV) brain stem areas. In the A1 region in (b), the raphe nucleus (R) and the nucleus of the solitary tract (NTS) project to the sympathetic motor neurones. After sympathetic denervation, there is no labelling of PRV in the IML (c). In the brain stem (d), neurones are clearly visible in the parasympathetic motor nuclei: the DMV and caudal part of the ambiguous nucleus (AMB). CC, Central canal. Scale bar = 0.5 mm (a and c), and 0.4 mm (b and d). Reproduced with permission from Kreier et al. (22).

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With respect to steroid hormone metabolism, WAT has an important role in the conversion of the adrenal androgen androstenedione to testosterone, of oestrone to oestradiol and of androgens to oestrogens. In addition, it is involved in glucocorticoid metabolism. Specifically, the enzyme type 1 11-β hydroxysteroid dehydrogenase (11-βHSD-1) is expressed in WAT and converts the inactive glucocorticoid cortisone to cortisol. Transgenic mice overexpressing 11-βHSD-1 develop visceral obesity and insulin-resistant diabetes mellitus in combination with hyperlipidemia (7). Thus, increased adipocyte 11-βHSD-1 activity may contribute to visceral obesity and the metabolic syndrome by local glucocorticoid production. Fat redistribution as a result of glucocorticoid excess is clinically well-known in Cushing's syndrome. However, the mechanism of glucocorticoid-induced fat redistribution has not been identified.

WAT was recently shown to produce additional hormones. It expresses and releases resistin, which, upon exogenous administration, impairs glucose tolerance and insulin action in normal mice (8). Increased resistin serum concentrations have been found in mouse models of obesity. A recent study suggested that noncoding single nucleotide polymorphisms in the human resistin gene may influence insulin sensitivity in interaction with body mass index (9). Another recently identified WAT-derived hormone is adiponectin, also known as adipocyte complement-related protein (Acrp30). It reduces insulin resistance in mouse models for obesity and lipoatrophy (10) and has been reported to reduce hepatic glucose production in intact mice (11).

Adipose tissue expresses proteins from the renin–angiotensin system as well as enzymes involved in the conversion from angiotensinogen to angiotensin II (12). Finally, WAT secretes inflammatory cytokines such as tumour necrosis factor-α and interleukin-6, and a number of coagulation and complement factors which may be of interest in view of the association between obesity and cardiovascular risk (13).

WAT: a metabolic organ

  1. Top of page
  2. Abstract
  3. WAT: a traditional endocrine gland
  4. WAT: a metabolic organ
  5. WAT: getting nervous
  6. Conclusion
  7. References

WAT stores massive amounts of triglycerides. These are derived from fatty acids taken up from the plasma. These fatty acids can be derived from plasma free fatty acids and from plasma triglycerides as a result of the local activity of the enzyme lipoprotein lipase. Fatty acids can also be synthesized within adipocytes de novo from glucose. Triglycerides stored within adipose tissue are continuously being hydrolysed into fatty acids and glycerol by the enzyme hormone sensitive lipase. These fatty acids can be either reesterified into triglycerides or released into the plasma.

Insulin and epinephrine are the main regulators of adipose tissue metabolism, whereas other factors such as cortisol and growth hormone exert less powerful effects. Insulin stimulates glucose and fatty acid uptake in adipose tissue and simultaneously inhibits hormone sensitive lipase, and thus lipolysis. Conversely, epinephrine increases lipolysis through stimulation of hormone sensitive lipase.

WAT: getting nervous

  1. Top of page
  2. Abstract
  3. WAT: a traditional endocrine gland
  4. WAT: a metabolic organ
  5. WAT: getting nervous
  6. Conclusion
  7. References

Sympathetic innervation

A number of observations have clearly shown that WAT is innervated by sympathetic endings of the autonomic nervous system. Surgical sympathectomy reduces lipolysis in the denervated WAT depot. Conversely, electrical stimulation of sympathetic nerve endings stimulates lipolysis and the release of free fatty acids (FFA). This effect can be blocked by sympathectomy and is mediated by β-adrenergic receptors (14). These experiments indicate a lipolytic effect of sympathetic stimulation of WAT. Studies in dogs confirmed that pulsatile secretion of FFA in the visceral fat compartment reflects changes in neural activity, rather than pulsatile changes in insulin concentrations in plasma (15). Accordingly, lipolysis of the subcutaneous tissue of the thigh in humans is partly under neural control and can be stimulated by electrical stimulation of the lateral cutaneous femoral nerve; this response is reduced in obese women (16).

Sympathetic innervation of WAT has been suggested to play a physiological role in the adaptation to prolonged fasting because norepinephrine turnover in WAT, but not in brown adipose tissue, increases in fasted rats (17). Patel et al. (18) showed increased norepinephrine spillover in abdominal subcutaneous WAT in healthy subjects after a 72-h fast, also pointing to a role for an increased sympathetic tone in lipid metabolism during fasting.

Studies in Siberian hamsters using pseudorabies virus (PRV) as a trans-synaptic retrograde neural tracer have partially elucidated the CNS origins of the sympathetic innervation of WAT depots (19). After inoculation in WAT, PRV-infected neurones were present in the spinal cord, brain stem, midbrain and forebrain areas. Within the hypothalamus, labelled neurones occurred in the suprachiasmatic nucleus (SCN), which contains the biological clock of the brain that controls daily changes in autonomic nervous system activity (20) (Fig. 1a). Highly selective lesions of the SCN in rats abolished the diurnal variation in serum concentrations of leptin. This effect was independent of diurnal changes in serum corticosterone or the diurnal pattern of food intake. Moreover, the mean serum concentrations of leptin were increased by SCN lesions indicating a possible inhibitory control of WAT via its autonomic innervation (21). Finally, we documented that these lesions also increased mRNA levels of leptin in WAT, indicating that the CNS affects gene expression in WAT. Thus, sympathetic innervation of WAT modulates hormone production by WAT in addition to its well-established stimulatory role in lipolysis.

Parasympathetic innervation

Recent neuroanatomical studies in rats have demonstrated parasympathetic innervation of WAT in rats. After selective sympathetic denervation and subsequent PRV inoculation in intra-abdominal WAT, intense PRV labelling was present in the dorsal motor nucleus of the vagal nerve (DMV) (Figs 1a,b) (22). In these studies, retrograde transneuronal labelling of PRV was detected immunocytochemically 4–5 days after inoculation. The physiological role of this parasympathetic input was assessed by combining selective vagotomy of a unilateral retroperitoneal fat pad (the contralateral fat pad serving as a control) with a hyperinsulinemic euglycemic clamp and with reverse transcriptase-polymerase chain reaction analysis. Vagotomy reduced both insulin-dependent glucose uptake and FFA uptake by 30–40% compared to the contralateral fat pad. By contrast, the activity of the catabolic enzyme hormone sensitive lipase (HSL) increased by approximately 50% in the same experiment (Fig. 2). Thus, parasympathetic innervation increases insulin sensitivity considerably. Consequently, insulin sensitivity is not a static phenomenon, but may vary under different conditions. In addition, parasympathetic input affects hormone synthesis in WAT as evident from the effects of selective vagotomy on mRNA expression of resistin and leptin (22).

image

Figure 2. Changes in glucose and free fatty acid (FFA) uptake and in activity of the catabolic enzyme hormone sensitive lipase (HSL) in adipose tissue after parasympathetic denervation. The left retroperitoneal fat pad was either parasympathetically denervated (n = 6) or sham operated (n = 6). Using a hyperinsulinemic euglycemic clamp, the uptake of 3H-2-deoxy-d-glucose and 14C-palmitate and the activity of HSL were assessed. Under these hyperinsulinemic conditions, glucose uptake in the denervated fat pad was reduced by 33% (P = 0.02) and fatty acid by 36% (P = 0.02). HSL activity was increased by 51% (P = 0.03) without any changes in sham-operated animals. Thus, parasympathetic denervation of adipose tissue shifts the metabolism to a catabolic state: uptake of substrate is reduced while lipolysis increases. Values are expressed as percentage change compared to contralateral, intact side. For original data, see Kreier et al. (22).

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Differential autonomic innervation of intra-abdominal and subcutaneous WAT; clinical implications

After simultaneous injection of two different tracers in different WAT compartments, the label appeared to be localized in the same nuclei of the autonomic nervous system but in different sets of neurones. Vagal motor neurones in the DMV projecting to intra-abdominal fat pads tended to be localized more medially to neurones projecting to subcutaneous WAT. Moreover, the sympathetic motor neurones in the spinal cord projecting to intra-abdominal or subcutaneous fat depots appeared to be separate sets of neurones (22). Thus, we have identified a neuroanatomical basis for differentiation between intra-abdominal and subcutaneous fat. Therefore, differences in body fat distribution (visceral versus subcutaneous fat) may reflect differential activities of somatotopically organized autonomic neurone sets in the CNS (Fig. 3), representing a physiological model in which determinants of body fat distribution (sex steroids, glucocorticoids) may act via the CNS. Moreover, this concept may accelerate our understanding of the association between visceral obesity on the one hand and cardiovascular morbidity and insulin resistance on the other.

image

Figure 3. Schematic representation of adipose tissue as an innervated endocrine gland. White adipose tisue produces hormones (endocrine signals) in addition to fatty acids and glycerol (metabolic signals). These signals are transported via the circulation and can be detected in the hypothalamus, inducing neuroendocrine responses (e.g. in the hypothalamus-pituitary-thyroid axis via thyrotropin-releasing hormone containing neurones), behavioural responses (e.g. eating behaviour) and autonomic responses (e.g. heart rate). The hypothalamus has autonomic connections with brain stem nuclei that innervate adipose tissue both via sympathetic and parasympathetic fibres. Both branches have metabolic and molecular effects in adipose tissue. There is a marked somatotopy in the brain stem and spinal cord: separate neurone sets innervate either the subcutaneous or the intra-abdominal fat compartment. This may be the neuro-anatomical basis for fat redistribution induced by sex steroids, or glucocorticoids.

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Multidrug antiretroviral regimens including human immunodeficiency virus-1 (HIV-1) protease inhibitors are associated with hypertriglyceridemia, insulin resistance and a redistribution of WAT, leading to visceral obesity and wasting of subcutaneous (e.g. facial) fat. A number of studies have addressed the hypothesis that this is due to hypercortisolism but no confirmation has been reported. For example, Yanovski et al. (23) reported normal diurnal cortisol secretion, normal cortisol secretory dynamics upon stimulation with CRH, normal cortisol-binding globulin levels, and normal glucocorticoid receptor number and affinity in HIV positive patients with evidence of protease inhibitor-associated lipodystrophy. This study confirmed initial reports of normal urinary free cortisol excretion and normal dexamethasone suppression in patients with this syndrome (24). Because a number of the available antiretroviral agents, including protease inhibitors, demonstrate consistent penetration into the cerebrospinal fluid (25), we propose that the somatotopical organization of autonomic innervation of intra-abdominal and subcutaneous WAT may be involved in the pathogenesis of AIDS lipodystrophy (26). In accordance with this hypothesis, we have found increased norepinephrine secretion in conjunction with increased lipolysis in patients with AIDS lipodystrophy, at least suggesting alterations in autonomic nerve activity (27).

Conclusion

  1. Top of page
  2. Abstract
  3. WAT: a traditional endocrine gland
  4. WAT: a metabolic organ
  5. WAT: getting nervous
  6. Conclusion
  7. References

By contrast to earlier beliefs, WAT is not merely a triglyceride store. Adipocytes synthesize and release a large number of hormones. Some of these newly discovered hormones have feedback effects on the hypothalamus, triggering neuroendocrine, metabolic and behavioural effects. The autonomic nervous system has both sympathetic and parasympathetic outflow to WAT. This innervation plays an important role in adipocyte metabolism, in insulin sensitivity and in hormone synthesis and release by WAT. Intra-abdominal and subcutaneous fat depots are innervated by different sets of neurones within autonomic nuclei in the spinal cord and brain stem. This somatotopy represents a neuroanatomical model for the largely unexplained effects of sex steroids and glucocorticoids on fat distribution. In addition, it may also be involved in the pathogenesis of fat redistribution syndromes.

References

  1. Top of page
  2. Abstract
  3. WAT: a traditional endocrine gland
  4. WAT: a metabolic organ
  5. WAT: getting nervous
  6. Conclusion
  7. References
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