Role of GPCRs in regulation of metabolism
Obesity is a disease defined as “abnormal or excessive fat accumulation that presents a health risk, with a body mass index (BMI) over 30” (World Health Organization). It is linked to several metabolic problems, including type 2 diabetes and cardiovascular diseases, which contribute to significant morbidity, mortality and increased healthcare costs (Heymsfield and Wadden 2017). Obesity is associated with abnormal regulation of appetite (Hopkins, Beaulieu et al. 2000, Suzuki, Jayasena et al. 2012), and in the human body, the central control of food intake takes place in the hypothalamus (Hopkins, Beaulieu et al. 2000, Suzuki, Jayasena et al. 2012). As such, signalling mediated by hypothalamus-expressed membrane proteins from the GPCR family has been shown to regulate food intake and metabolism (Barella, Jain et al. 2021, Deng, Deng et al. 2021).
Of GPCRs, the proopiomelanocortin (POMC)/melanocortin 4 receptor (MC4R) circuit plays a key role in appetite regulation (Adan, Tiesjema et al. 2006, Baldini and Phelan 2019, Brouwers, de Oliveira et al. 2021). Ligand-induced and constitutive activity of wild-type or gain-of-function mutants of MC4R lead to the activation of transducer Gs proteins and an increase in intracellular second messenger cAMP production, which results in reduced food intake (Adan, Tiesjema et al. 2006, Tao 2014, Lotta, Mokrosinski et al. 2019). Furthermore, brain-expressed agouti-related protein (AgRP) acts as an inverse agonist of MC4R blocking its signalling (Nijenhuis, Oosterom et al. 2001). Interestingly, non-specific Gs stimulation in AgRP neurons leads to increased food intake. This suggests that understanding the details of GPCR-G protein signalling can be key in elucidating molecular mechanisms of the development of obesity (Nakajima, Cui et al. 2016). A different GPCR that has recently been implicated in controlling body weight is GPR3. This constitutively-active orphan GPCR has been reported to promote lipolysis in adipocytes via activating Gs (Sveidahl Johansen, Ma et al. 2021). Along these lines, there are several other Gs-coupled receptors expressed in the hypothalamus whose functions have not been elucidated.
Of GPCRs, the proopiomelanocortin (POMC)/melanocortin 4 receptor (MC4R) circuit plays a key role in appetite regulation (Adan, Tiesjema et al. 2006, Baldini and Phelan 2019, Brouwers, de Oliveira et al. 2021). Ligand-induced and constitutive activity of wild-type or gain-of-function mutants of MC4R lead to the activation of transducer Gs proteins and an increase in intracellular second messenger cAMP production, which results in reduced food intake (Adan, Tiesjema et al. 2006, Tao 2014, Lotta, Mokrosinski et al. 2019). Furthermore, brain-expressed agouti-related protein (AgRP) acts as an inverse agonist of MC4R blocking its signalling (Nijenhuis, Oosterom et al. 2001). Interestingly, non-specific Gs stimulation in AgRP neurons leads to increased food intake. This suggests that understanding the details of GPCR-G protein signalling can be key in elucidating molecular mechanisms of the development of obesity (Nakajima, Cui et al. 2016). A different GPCR that has recently been implicated in controlling body weight is GPR3. This constitutively-active orphan GPCR has been reported to promote lipolysis in adipocytes via activating Gs (Sveidahl Johansen, Ma et al. 2021). Along these lines, there are several other Gs-coupled receptors expressed in the hypothalamus whose functions have not been elucidated.
Research questions
Are there also other Gs-coupled brain-expressed GPCRs which regulate metabolism?
Is there a crosstalk between GPCRs involved in governing the food intake?
Is there a crosstalk between GPCRs involved in governing the food intake?
Project includes
- development of biophysical readouts to test for ligand binding, conformational changes, and activation of wild-type and mutated selected orphan GPCRs
- discovery of new selective ligands of orphan GPCRs using in silico screening of large-scale compound libraries
- demonstration that orphan GPCR-mediated signalling affects food intake and autophagy in cultured cells typifying hypothalamic neurons and brain organoids (central control of metabolism); glucose and lipid metabolism in muscles and liver in vitro and in vivo (peripheral control of metabolism)
