GPR101 is an orphan class A GPCR that is highly expressed in the nucleus accumbens and the hypothalamus and has constitutive Gs and Gq activity.199 GPR101 gene duplication or mutation modulates its constitutive activity, rendering GPR101 a promising target for metabolic diseases.200 Recent studies have identified AA-14 (15) (Fig. 14) as an allosteric agonist of GPR101, demonstrating robust Gs activation activity and high subtype selectivity.201 In vivo studies have shown that AA-14 exerts rejuvenating effects by activating GPR101 in the pituitary. The gene discussed is GPR101; the disease is metabolic disease.