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

Opsin3 (Opn3) is a transmembrane heptahelical G-protein-coupled receptor
(GPCR) with the potential to produce a non-visual photoreceptive effect.
Interestingly, anatomical profiling of GPCRs reveals that Opn3 mRNA is
highly expressed in adipose tissue. The photosensitive functions of Opn3
in mammals are poorly understood, and whether Opn3 has a role in fat is
entirely unknown. In this study, we found that Opn3-knockout (Opn3-KO)
mice were prone to diet-induced obesity and insulin-resistance. At the
cellular level, Opn3-KO brown adipocytes cultured in darkness had
decreased glucose uptake and lower nutrient-induced mitochondrial
respiration than wild-type (WT) cells. Light exposure promoted
mitochondrial activity and glucose uptake in WT adipocytes but not in
Opn3-KO cells. Brown adipocytes carrying a defective mutation in Opn3’s
putative G-protein-binding domain also exhibited a reduction in glucose
uptake and mitochondrial respiration in darkness. Using RNA sequencing, we
identified several novel light-sensitive and Opn3-dependent molecular
signatures in brown adipocytes. Importantly, direct exposure of BAT to
light in living mice significantly enhanced thermogenic capacity of BAT,
and this effect was diminished in Opn3-KO animals. These results uncover a
previously unrecognized cell-autonomous, light-sensing mechanism in brown
adipocytes via Opn3-GPCR signaling that can regulate fuel metabolism and
mitochondrial respiration in vitro and thermogenesis in vivo. Our work
also provides a potential basis for developing light-based treatments for
obesity and its related metabolic disorders.