Immunomodulatory leptin receptor+ Sympathetic Associated Perineurial Cells protect against obesity

Thesis

Obesity is a culmination of long-term energy imbalance, resulting in the storage of excess fats as triglycerides in adipose tissues (ATs). Sympathetically innervated ATs are key sites of both energy storage and hormone production. Leptin is one such hormone produced by adipocytes, released in proportion to AT mass. Leptin acts in the hypothalamus to diminish hunger and increase sympathetic drive onto ATs. This increase in sympathetic-derived norepinephrine stimulates adipocyte lipolysis and thermogenesis, providing a neuroendocrine negative feedback loop which broadly controls energy storage and energy expenditure. Obesity is closely associated with chronic, low- grade AT inflammation, mirrored by an increase in pro-inflammatory and a concomitant decrease in anti-inflammatory AT immune cells. Here, we reveal a novel population of Leptin receptor+ perineurial cells ensheathing AT sympathetic neurons, which express the sympathetic neurotransmitter receptor Adrb2, and produce key anti-inflammatory cytokines, including IL-33. We show that mice with a perineurial cell-specific loss of IL-33 gain more weight when fed high-fat diet despite comparable food intake - indicative of metabolic dysfunction. In the pre-obese state, a loss of perineurial cell derived IL-33 reduces the frequency of anti-inflammatory regulatory immune cells, including regulatory T cells (Tregs) and eosinophils specifically within the brown adipose tissue (BAT). Along with this shift in BAT-populating immune cells, we show that these mice have impaired adaptive BAT thermogenesis, predisposing to obesity with metabolic challenge. Furthermore, we show that SAPC-specifc deletion of Adrb2 increases IL-33 production in the brown adipose tissue, indicating that cytokine production by SAPCs may also be regulated by the sympathetic nervous system. Together, this firmly implicates Sympathetic Associated Perineurial Cells in the regulation of adipose tissue homeostasis, and highlights a novel cellular target in the prevention and treatment of obesity.

Authors: Haberman, E

• DOI: 10.5287/ora-8ryxoqkob
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: IL-33; tregs; neuroimmunometabolism; thermogenesis; brown adipose tissue; leptin receptor; obesity; perineurial cells; sympathetic nerves; eosinophils; ILC2s
• Subjects: Neuroimmunometabolism