Cell-autonomous light sensitivity via Opsin3 regulates fuel utilization in brown adipocytes

Area of Science:

• Metabolic research
• Adipose tissue biology
• GPCR signaling

Background:

• Opsin3 (Opn3) is a G protein-coupled receptor (GPCR) with unknown functions in mammals.
• Opn3 mRNA is highly expressed in adipose tissue, suggesting a role in fat metabolism.
• The role of Opn3 in metabolic disorders like obesity and insulin resistance is unexplored.

Purpose of the Study:

• To investigate the function of Opn3 in brown adipocytes and its role in diet-induced obesity and insulin resistance.
• To elucidate the molecular mechanisms by which Opn3 regulates fuel metabolism and mitochondrial respiration.
• To determine if light-sensing by Opn3 in brown adipose tissue influences thermogenesis.

Main Methods:

• Generated and analyzed Opn3-knockout (Opn3-KO) mice and brown adipocytes.
• Assessed glucose uptake and mitochondrial respiration in wild-type (WT) and Opn3-KO adipocytes under different light conditions.
• Utilized RNA-sequencing to identify Opn3-dependent molecular signatures.
• Measured brown adipose tissue (BAT) thermogenic capacity in vivo.

Main Results:

• Opn3-KO mice exhibited increased susceptibility to diet-induced obesity and insulin resistance.
• Opn3-deficient brown adipocytes showed reduced glucose uptake and mitochondrial respiration, which light exposure could not rescue.
• Light exposure enhanced mitochondrial activity and glucose uptake in WT adipocytes but not in Opn3-KO cells.
• Direct light exposure to BAT in vivo significantly increased thermogenic capacity, an effect blunted in Opn3-KO mice.

Conclusions:

• Opn3 acts as a cell-autonomous light sensor in brown adipocytes, regulating fuel metabolism and mitochondrial respiration.
• Opn3 signaling in BAT is crucial for light-mediated enhancement of thermogenic capacity.
• These findings reveal a novel mechanism for controlling energy expenditure and offer potential for light-based obesity treatments.