Genetics-based manipulation of adipose tissue sympathetic innervation

Abstract

There is renewed interest in leveraging the thermogenic capacity of brown adipose tissue (BAT) and browning of white adipose tissue (WAT) to improve energy balance and prevent obesity. In addition to these effects on energy expenditure, both BAT and WAT secrete large numbers of hormones and cytokines that play important roles in maintaining metabolic health. Both BAT and WAT are densely innervated by the sympathetic nervous system (SNS) and this innervation is crucial for BAT thermogenesis and WAT browning, making it a potentially interesting target for manipulating energy balance and treatment of obesity and metabolic disease. Peripheral neuromodulation in the form of electrical manipulation of the SNS and parasympathetic nervous system (PSNS) has been used for the management of pain and many other conditions, but progress is hampered by lack of detailed knowledge of function-specific neurons and nerves innervating particular organs and tissues. Therefore, the goal of the National Institutes of Health (NIH) Common Fund project "Stimulating Peripheral Activity to Relieve Conditions (SPARC)" is to comprehensively map both anatomical and neurochemical aspects of the peripheral nervous system in animal model systems to ultimately guide optimal neuromodulation strategies in humans. Compared to electrical manipulation, neuron-specific opto- and chemogenetic manipulation, now being extensively used to decode the function of brain circuits, will further increase the functional specificity of peripheral neuromodulation.

Browning of white fat: agents and implications for beige adipose tissue to type 2 diabetes

“…Cold exposure induced browning in mice has also been studied by Vitali et al (2012) and they suggest that the density of sympathetic nerves innervating WAT is one of the key features for the browning effect to take place [81]. However, very little is known about SNS innervation in WAT browning and beige adipocytes, underlining it as one important future research line [21].…”

Dietary Options for Rodents in the Study of Obesity

“…Importantly, it has been demonstrated that the levels of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter that suppresses neuron excitability, are increased in BAT of HFD-fed mice promoting BAT disfunction [118]. All these exiting results provide new insights into innervation patterns and nerve plasticity in adipose depots, suggesting that neuromodulation could become an essential strategy to explore new ways to treat obesity (reviewed in [119][120][121][122]). Additional research should be done to elucidate nerve subtypes and their tissue functions in order to understand the physiological crosstalk between brain and peripheral tissues and their contribution to maintain energy balance.…”

Brown and Brite: The Fat Soldiers in the Anti-obesity Fight

“…Given our increased understanding of the metabolic effects of the activated BAT, novel approaches to increase its activity are being explored. Using optical and electrical genetic stimulation of specific neurons in the sympathetic nervous offers an interesting option (François et al, 2017) to modulate the activity of BAT or to induce browning in specific depots. Oral genetic therapy to manipulate BAT has been reported in mice (Huang et al, 2016) and was able to increase BAT mass and activity.…”