ADGRA1 negatively regulates energy expenditure and thermogenesis through both sympathetic nervous system and hypothalamus–pituitary–thyroid axis in male mice

Abstract

Adhesion G protein-coupled receptor A1 (ADGRA1, also known as GPR123) belongs to the G protein-coupled receptors (GPCRs) family and is well conserved in the vertebrate lineage. However, the structure of ADGRA1 is unique and its physiological function remains unknown. Previous studies have shown that Adgra1 is predominantly expressed in the central nervous system (CNS), indicating its important role in the transduction of neural signals. The aim of this study is to investigate the central function of Adgra1 in vivo and clarify its physiological significance by establishing an Adgra1-deficient mouse (Adgra1−/−) model. The results show that Adgra1−/− male mice exhibit decreased body weight with normal food intake and locomotion, shrinkage of body mass, increased lipolysis, and hypermetabolic activity. Meanwhile, mutant male mice present elevated core temperature coupled with resistance to hypothermia upon cold stimulus. Further studies show that tyrosine hydroxylase (TH) and β3-adrenergic receptor (β3-AR), indicators of sympathetic nerve excitability, are activated as well as their downstream molecules including uncoupling protein 1 (UCP1), coactivator 1 alpha (PGC1-α) in brown adipose tissue (BAT), and hormone-sensitive lipase (HSL) in white adipose tissue (WAT). In addition, mutant male mice have higher levels of serum T3, T4, accompanied by increased mRNAs of hypothalamus–pituitary–thyroid axis. Finally, Adgra1−/− male mice present abnormal activation of PI3K/AKT/GSK3β and MEK/ERK pathways in hypothalamus. Overexpression of ADGRA1 in Neuro2A cell line appears to suppress these two signaling pathways. In contrast, Adgra1−/− female mice show comparable body weight along with normal metabolic process to their sex-matched controls. Collectively, ADGRA1 is a negative regulator of sympathetic nervous system (SNS) and hypothalamus–pituitary–thyroid axis by regulating PI3K/AKT/GSK3β and MEK/ERK pathways in hypothalamus of male mice, suggesting an important role of ADGRA1 in maintaining metabolic homeostasis including energy expenditure and thermogenic balance.

Effect of High-Intensity Interval Training on Fatty Infiltration After Delayed Rotator Cuff Repair in a Mouse Model

“…TH is the rate-limiting enzyme in the synthesis of norepinephrine, a sympathetic neurotransmitter. 54 Increased expression of TH indicates activation of local sympathetic nerve fibers, 13 , 54 and increased expression of UCP1 indicates activation of BAT or beige fat. 23 Previous research found some interesting interactions between sympathetic nerves and adipose tissues.…”

High-intensity interval training improves fatty infiltration in the rotator cuff through the β3 adrenergic receptor in mice

“…Tyrosine hydroxylase is the rate-limiting enzyme in the synthesis of norepinephrine, a sympathetic neurotransmitter. 48 Increased expression of tyrosine hydroxylase indicates activation of local sympathetic nerve fibres. 40 , 48 Increased expression of UCP1 indicates white fat browning or activation of brown/beige-like adipose tissue.…”

“… 48 Increased expression of tyrosine hydroxylase indicates activation of local sympathetic nerve fibres. 40 , 48 Increased expression of UCP1 indicates white fat browning or activation of brown/beige-like adipose tissue. 17 We also detected tyrosine hydroxylase and UCP1 expression in other beige/brown fat depots by immunofluorescence to confirm this HIIT effect.…”

Extracellular vesicles in cancer cachexia: deciphering pathogenic roles and exploring therapeutic horizons

“…GDF15 is known for its role in mediating anorexic responses, and its presence in EVs suggests a pathway by which tumors can systemically affect appetite and energy balance. Additionally, EVs can influence the sympathetic nervous system’s activity [ 128 ], leading to increased energy expenditure [ 129 ] and contributing to muscle wasting [ 130 ]. This interaction further exemplifies the complex ways in which EVs can modulate systemic metabolic responses in cancer cachexia.…”