Separate and shared sympathetic outflow to white and brown fat coordinately regulates thermoregulation and beige adipocyte recruitment

Abstract

White adipose tissue (WAT) and brown adipose tissue (BAT) are innervated and regulated by the sympathetic nervous system (SNS). It is not clear, however, whether there are shared or separate central SNS outflows to WAT and BAT that regulate their function. We injected two isogenic strains of pseudorabies virus, a retrograde transneuronal viral tract tracer, with unique fluorescent reporters into interscapular BAT (IBAT) and inguinal WAT (IWAT) of the same Siberian hamsters to define SNS pathways to both. To test the functional importance of SNS coordinated control of BAT and WAT, we exposed hamsters with denervated SNS nerves to IBAT to 4°C for 16-24 h and measured core and fat temperatures and norepinephrine turnover (NETO) and uncoupling protein 1 (UCP1) expression in fat tissues. Overall, there were more SNS neurons innervating IBAT than IWAT across the neuroaxis. However, there was a greater percentage of singly labeled IWAT neurons in midbrain reticular nuclei than singly labeled IBAT neurons. The hindbrain had ~30-40% of doubly labeled neurons while the forebrain had ~25% suggesting shared SNS circuitry to BAT and WAT across the brain. The raphe nucleus, a key region in thermoregulation, had ~40% doubly labeled neurons. Hamsters with IBAT SNS denervation maintained core body temperature during acute cold challenge and had increased beige adipocyte formation in IWAT. They also had increased IWAT NETO, temperature, and UCP1 expression compared with intact hamsters. These data provide strong neuroanatomical and functional evidence of WAT and BAT SNS cross talk for thermoregulation and beige adipocyte formation.

Leptin and brain–adipose crosstalks

“…Early studies showed that manipulations of the VMH altered temperature and noradrenaline turnover in BAT 183,184 and fat utilization in WAT 185–188 ; however, there was no evidence of direct connections between the VMH and BAT 108 . However, a recent study using PRV tract tracing from BAT shows a substantial percentage of PRV-labelled neurons in the VMH 109 , helping to account for earlier works showing a functional connection between the VMH and BAT 185–188 .…”

“…Retrograde transneuronal viral tracing using pseudorabies virus (PRV) was instrumental in mapping the sympathetic innervation of BAT 107,108 . Sympathetic preganglionic neurons innervating interscapular BAT are located in the IML of the T1–T6 spinal segments 109,110 , and the sympathetic postganglionic neurons that project into interscapular BAT are located in the T1–T5 paravertebral ganglia, with a large number in the stellate ganglion 111 (BOX 2). Again, these data must be interpreted with caution, as PRV can infect different neuronal terminals.…”

“…The understanding of the innervation patterns of the different fat depots is still evolving, and more studies are needed to better characterize and map how the brain and adipose tissues communicate with each other. Using a combination of fluorescent tract tracers and retrograde labelling (using pseudorabies virus (PRV)), sympathetic thoracolumbar ganglia were observed to project to both gonadal white adipose tissue (WAT) and inguinal WAT in Siberian hamsters and rats 109,208 (FIG. 4).…”

“…Thus, coupling tract tracers and retrograde labelling to TH immunostaining will be useful to further determine the nature of the SNS ganglia projection to adipose tissues. Interestingly, the SNS ganglia that innervate inguinal WAT are similar to those innervating brown adipose tissue (BAT) (at T1–T3 and T12–L3 vertebral levels) 109 , whereas the SNS ganglia that innervate mesenteric and inguinal WAT were shown to exhibit some regional differences throughout the T5–L13 sympathetic chain levels 208 (FIG. 4).…”

Lipolysis in Brown Adipocytes Is Not Essential for Cold-Induced Thermogenesis in Mice

“…Mice with BAT paucity (Schulz et al, 2013) or hamsters with iBAT sympathetic denervation (Nguyen et al, 2016) also had enhanced WAT browning, but this may be due to a general loss of BAT functions or thermogenic stimulation. Here we revealed a different mechanism in regulation of WAT browning, i.e.…”