A Tale of Three Systems: Toward a Neuroimmunoendocrine Model of Obesity

Abstract

The prevalence of obesity is on the rise. What was once considered a simple disease of energy imbalance is now recognized as a complex condition perpetuated by neuro- and immunopathologies. In this review, we summarize the current knowledge of the neuroimmunoendocrine mechanisms underlying obesity. We examine the pleiotropic effects of leptin action in addition to its established role in the modulation of appetite, and we discuss the neural circuitry mediating leptin action and how this is altered with obesity, both centrally (leptin resistance) and in adipose tissues (sympathetic neuropathy). Finally, we dissect the numerous causal and consequential roles of adipose tissue macrophages in obesity and highlight recent key studies demonstrating their direct role in organismal energy homeostasis.

Keywords: adipose; innervation; leptin; macrophage; neuroimmune; sympathetic.

Figure 1. The systemic triad regulating energy expenditure.

The sympathetic nervous, immune, and adipose systems converge in bi- and tri-directional manners to regulate systemic metabolism in humans. Adrenergic signalling (norepinephrine; NE), emanating from sympathetic nerve fibres, has various immunomodulatory effects and triggers lipolysis in adipose tissue. Sympathetic fibre-associated macrophages (SAMs) catabolise NE to inhibit this process and thereby inhibit weight loss. Adipose tissue-derived leptin is the afferent signal in a neuro-endocrine negative feedback loop that controls appetite and feeding. Leptin also has demonstrable energy expending effects in the periphery as evidenced by pair-feeding studies and is a potent immunomodulator of various innate immune cells. The adipose tissue itself is a dynamic endocrine organ, populated largely by macrophages in the obese state which promote inflammation and predispose to insulin resistance and type 2 diabetes.

Figure 2. Neuroimmunity in Obesity.

Central panel: The neuroendocrine loop of leptin action, where leptin constitutes the afferent arm and sympathetic neurons make up the efferent arm in the brain-adipose tissue axis. Top panels, lean (left) and obese (right): Leptin signalling results in the phosphorylation of STAT3 in POMC and AgRP neurons in the arcuate nucleus (ARC), which upregulate POMC and downregulate AgRP, respectively. Collectively, leptin signalling in the ARC results in activation of MC4-R⁺ neurons within the paraventricular nucleus (PVN), and a subsequent increase in sympathetic drive onto peripheral adipose tissues. BDNF neurons within the PVN also act downstream of ARC leptin signalling, and are required for the regulation of adipose tissue innervation. It is not clear whether BDNF and MC4-R neurons represent one or two populations within the PVN. Chronic leptin signalling in obesity increases SOCS3 – a known suppressor of leptin signalling – in POMC and AgRP neurons. Coupled with hypothalamic inflammation and ER stress, this is likely causative of central leptin resistance and impaired responses downstream of ARC leptin signalling. Middle panels, lean (left) and obese (right): Sympathetic neuron-Associated Macrophages (SAMs) act as a sink for norepinephrine (NE) in adipose tissues through Slc6a2-mediated uptake and MAOA degradation of NE, modulating lipolysis in WAT. Few SAMs associate with the dense sympathetic AT innervation in the lean state. Sympathetic innervation is reduced in obesity, and SAMs are massively recruited to WAT neurons, reducing NE-mediated adipocyte lipolysis. Bottom WAT panels, lean (left) and obese (right): In the lean state, yolk sac-derived, adipose tissue macrophages (ATMs) and Tregs maintain an anti-inflammatory state in AT. Bone marrow-derived pro-inflammatory ATMs are recruited with obesity, initiating chronic, low-level adipose tissue inflammation. Bottom BAT panel (centre): In addition to reduced sympathetic drive, innervation of brown adipose tissue is reduced with obesity, resulting in a reduction in NE levels and a concomitant decrease in thermogenesis (left vs. right).