Notably, enhanced Ca 2+ cycling by S107, a chemical stabilizer for the RyR2-Calstabin interaction, potently stimulated UCP1-independent thermogenesis and protected Ucp1 null mice from hypothermia following cold exposure 10.

The Ca 2+ cycling thermogenesis is evolutionally conserved in humans, mice, and also pigs, a mammalian species that lack a functional UCP1 protein 10. We previously reported a UCP-independent mechanism in beige fat that involves ATP-dependent Ca 2+ futile cycling through Sarco/endoplasmic reticulum Ca 2+-ATPase2b (SERCA2b) and Ryanodine Receptor 2 (RyR2) 10. The recent identification of non-canonical UCP1-independent thermogenesis may offer unique opportunities to enhance adipose tissue thermogenesis 10, 11. Accordingly, identifying alternative pathways that stimulate fat thermogenesis, while avoiding cardiovascular risks, could lead to effective and safe therapeutic interventions for obesity. However, a major hurdle for applying ОІ3-AR agonists to the treatment of obesity is that, besides the poor bioavailability, pharmacological ОІ3-AR activation at an effective dose to achieve thermogenesis inevitably increases blood pressure as well 8, 9. Consistent with the model, a selective ОІ3-AR agonist, mirabegron, significantly promotes adipose tissue thermogenesis and resting metabolic rate by approximately 200вЂ‰kcal per day in adult humans 7. Accordingly, extensive efforts have been made to develop ОІ3-AR agonists as an anti-obesity medication that stimulates adipose tissue thermogenesis. The best-known stimulus of adipose tissue thermogenesis is cold: following cold exposure, noradrenaline (NA) released from the sympathetic nerve system (SNS) activates the ОІ3-adrenergic receptor (ОІ3-AR) and its downstream signaling pathway, including PKA and p38MAPK, which triggers adipose tissue thermogenesis through uncoupling protein 1 (UCP1) as well as UCP1-independent mechanisms 3, 4, 5, 6. Recent studies have illuminated the therapeutic potential of thermogenic fat for the treatment of metabolic disorders because impaired adipose thermogenesis is tightly associated with the development of obesity and insulin resistance, whereas activation of the thermogenic pathway potently improves metabolic health 1, 2. Non-shivering thermogenesis by thermogenic fat cells (brown and beige fat) plays a significant role in the regulation of whole-body energy homeostasis. The present study provides the first proof-of-concept that fat-specific cold mimetics via activating non-canonical thermogenesis protect against obesity. Significantly, the light-induced fat thermogenesis was sufficient to protect mice from diet-induced body-weight gain. The wireless optogenetics stimulation in the subcutaneous adipose tissue potently activates Ca 2+ cycling fat thermogenesis and increases whole-body energy expenditure without cold stimuli. To activate fat thermogenesis under tight spatiotemporal control without external stimuli, here, we report an implantable wireless optogenetic device that bypasses the ОІ-AR pathway and triggers Ca 2+ cycling selectively in adipocytes. However, systemic activation of the ОІ3-AR pathway inevitably increases blood pressure, a significant risk factor for cardiovascular disease, and, thus, limits its application for the treatment of obesity. Cold stimuli and the subsequent activation of ОІ-adrenergic receptor (ОІ-AR) potently stimulate adipose tissue thermogenesis and increase whole-body energy expenditure.

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