Neuropathy and neural plasticity in the subcutaneous white adipose depot.

Magdalena Blaszkiewicz,Amanda L Dubois,Jake W Willows,Kristy L Townsend,Katherine Motyl,Cory P Johnson,Benjamin Harrison,Kristen Dibello,Emma Paradie,Nicholas Banks,Merilla Michael,Lila L Lyons,Stephen Waible,Alessandro Bartolomucci

doi:10.1371/journal.pone.0221766

Magdalena Blaszkiewicz, Amanda L Dubois + Show 12 more

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https://doi.org/10.1371/journal.pone.0221766

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Abstract

The difficulty in obtaining as well as maintaining weight loss, together with the impairment of metabolic control in conditions like diabetes and cardiovascular disease, may represent pathological situations of inadequate neural communication between the brain and peripheral organs and tissues. Innervation of adipose tissues by peripheral nerves provides a means of communication between the master metabolic regulator in the brain (chiefly the hypothalamus), and energy-expending and energy-storing cells in the body (primarily adipocytes). Although chemical and surgical denervation studies have clearly demonstrated how crucial adipose tissue neural innervation is for maintaining proper metabolic health, we have uncovered that adipose tissue becomes neuropathic (ie: reduction in neurites) in various conditions of metabolic dysregulation. Here, utilizing both human and mouse adipose tissues, we present evidence of adipose tissue neuropathy, or loss of proper innervation, under pathophysiological conditions such as obesity, diabetes, and aging, all of which are concomitant with insult to the adipose organ as well as metabolic dysfunction. Neuropathy is indicated by loss of nerve fiber protein expression, reduction in synaptic markers, and lower neurotrophic factor expression in adipose tissue. Aging-related adipose neuropathy particularly results in loss of innervation around the tissue vasculature, which cannot be reversed by exercise. Together with indications of neuropathy in muscle and bone, these findings underscore that peripheral neuropathy is not restricted to classic tissues like the skin of distal extremities, and that loss of innervation to adipose may trigger or exacerbate metabolic diseases. In addition, we have demonstrated stimulation of adipose tissue neural plasticity with cold exposure, which may ameliorate adipose neuropathy and be a potential therapeutic option to re-innervate adipose and restore metabolic health.

Highlights

Since body weight regulation involves a precise balance between energy intake and energy expenditure, and requires coordination and control stemming from the central nervous system (CNS), the brain needs to adequately communicate with peripheral organs and tissues via peripheral nerves in order to maintain metabolic health
In order to investigate whether obesity/diabetes leads to adipose tissue neuropathy, we used BTBR mice with the ob/ob leptin-deficient mutation (MUT)
By 12 weeks of age, male BTBR MUT mice exhibited the expected increase in body weight when compared to BTBR +/+ wild type (WT) mice (Fig 1A), which was concurrent with increased subcutaneous adiposity (Fig 1B)

Summary

Introduction

Since body weight regulation involves a precise balance between energy intake and energy expenditure, and requires coordination and control stemming from the central nervous system (CNS), the brain needs to adequately communicate with peripheral organs and tissues via peripheral nerves in order to maintain metabolic health. The CNS is able to control energy expenditure by signaling motivation to exercise or seek certain foods, by driving sympathetic nervous system (SNS) activation of energy expending processes in the peripheral tissues of the body, and through receiving feedback from tissue sensory nerves, like those from adipose [1]. Sensory nerves in white adipose tissue (WAT) are thought to communicate the status of energy stores to the brain, in order to help regulate energy intake versus expenditure. BAT must utilize fatty acid fuels, which are both stored in the multilocular lipid droplets of brown adipocytes and are obtained via circulating lipids that are released from WAT through lipolysis, a sympathetic-mediated process [5,6]

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