TABLE 1.
Diverse functions of RTKs and their ligands in regulating metabolism.
| Receptor | Target | Phenotype | References |
| EGFR | |||
| EGFR | EGF protein treatment | Both increased insulin secretion, both decreased and increased glucose levels reported | Jansen et al., 2006; Lee et al., 2008 |
| Kinase dead EGFR | Decreased glucose levels | Li et al., 2018 | |
| EGFR inhibitor Erlotinib | Decreased blood glucose levels, improved glucose tolerance and insulin sensitivity | Li et al., 2018 | |
| EGFR inhibitor PD153035 | Improved NAFLD and glucose tolerance | Choung et al., 2019 | |
| Constitutively active EGFR | Increased plasma LDL cholesterol and triglycerides | Scheving et al., 2014 | |
| ErbB3/4 | NRG1 protein treatment | Improved glucose tolerance and insulin sensitivity, lowered blood glucose, reduced weight gain | Ennequin et al., 2014; Ennequin et al., 2015; Zhang et al., 2018 |
| Nrg4 global KO | More prone to develop diet-induced insulin resistance and hepatic steatosis, fibrosis and inflammation | Wang. G.-X. et al., 2014; Guo et al., 2017 | |
| NRG4 OE in adipose tissue | Improved diet-induced NASH | Guo et al., 2017 | |
| PDGFR | |||
| PDGFR | PDGFββ protein treatment | No change in blood glucose after protein treatment | Yuasa et al., 2004 |
| Partial loss of PDGFβ activity | Decreased glucose levels, improved insulin sensitivity, decreased insulin levels | Raines et al., 2011 | |
| PDGFRβ inducible global KO | Increased energy expenditure, alleviated diet-induced obesity, improved glucose metabolism | Onogi et al., 2017 | |
| PDGFR/Kit inhibitor Imatinib | Decreased blood glucose, increased insulin sensitivity and glucose disposal, elevated adiponectin levels, decreased cholesterol-induced atherosclerosis | Breccia et al., 2004; Veneri et al., 2005; Agerkvist et al., 2008; Fitter et al., 2010; Gómez-sámano et al., 2018; Pouwer et al., 2018 | |
| Kit | Kit heterozygotes | Increased glucose levels, impaired glucose tolerance | Krishnamurthy et al., 2007 |
| Kit mutation | Impaired glucose tolerance and insulin sensitivity, increased body mass and body fat, increased serum triglyceride levels, decreased energy expenditure | Huang et al., 2014 | |
| SCF global OE | Reduced weight gain, increased thermogenesis | Huang et al., 2014 | |
| CSF1R | CSF1-Fc protein treatment | Increased body weight | Gow et al., 2014 |
| CSF1-Fc protein treatment | No change in body weight | Pridans et al., 2018 | |
| FGFR | |||
| FGFR1 | FGF1 protein treatment | Decreased glucose levels without causing hypoglycemia, improved insulin sensitivity | Suh et al., 2014; Scarlett et al., 2016 |
| FGF1 KO | Impared glucose tolerance and insulin sensitivity | Jonker et al., 2012 | |
| FGF5 global KO | Developed fatty liver | Hanaka et al., 2014 | |
| FGF21 protein treatment | Decreased body weight, fat mass, glucose, lipid and insulin levels, increased | Kharitonenkov et al., 2005; Coskun et al., 2008; Xu et al., 2009 | |
| FGF21 KO | Suppressed browning of white adipose tissue | Fisher et al., 2012 | |
| FGF21 liver-specific KO | Impaired glucose tolerance and insulin sensitivity | Markan et al., 2014 | |
| FGF21 adipocyte-specific KO | No change in glucose tolerance and insulin sensitivity | Markan et al., 2014 | |
| FGFR1 adipose specific KO | Loss of FGF21-mediated lowering of glucose, insulin and triglycerides levels, body weight, and increase in energy expenditure; preserved functions of FGF19 treatments on decrease of glucose, insulin levels, and body weight | Adams et al., 2012b; Foltz et al., 2012 | |
| FGFR1/FGFR4 | FGF19 protein treatment | Decreased body weight, glucose and insulin levels, increase energy expenditure and glucose tolerance, decrease HPA axis activity, increased blood lipid levels | Tomlinson et al., 2002; Fu et al., 2004; Morton et al., 2013; Wu et al., 2013; Perry et al., 2015 |
| FGF15 KO | Impaired insulin sensitivity and elevated serum cholesterol. decreased liver fibrosis under high-fat diet | Schumacher et al., 2017 | |
| FGFR4 KO | Increased fat mass, increased circulating lipid levels | Huang et al., 2007 | |
| FGFR inhibitor PD173074 | Impaired glucose tolerance, increased food intake, increased plasma levels of norepinephrine and epinephrine | Ryan et al., 2013; Rojas et al., 2015 | |
| FGFR2 | FGF10 KO adipocytes | Impaired adipocyte differentiation | Sakaue et al., 2002; Asaki et al., 2004 |
| βKlotho adipose specific KO | Loss of FGF21-mediated acute glucose lowering effect but preserved functions of long term treatment of both FGF19 and FGF21 on lowering body weight, glucose and insulin levels, and hepatic triglycerides | Adams et al., 2012a; Ding et al., 2012; BonDurant et al., 2017; Lan et al., 2017 | |
| HGFR MET | βKlotho whole-body KO | Loss of FGF21-mediated increase in energy expenditure and lowering of body weight, fat mass, and insulin levels | Ding et al., 2012 |
| HGF global OE | Ameliorated fatty liver, increased serum triglyceride levels | Kosone et al., 2007 | |
| HGF OE in muscle | Improved glucose tolerance under high-fat diet | Sanchez-encinales et al., 2015 | |
| HGF OE in heart | Protected from high-fat diet induced body weight gain, improved insulin sensitivity | Muratsu et al., 2017 | |
| HGF antibody | Impaired glucose clearance | Muratsu et al., 2017 | |
| MET knockdown in liver | Impaired glucose clearance | Fafalios et al., 2011 | |
| MET KO in hepatocytes | No influence on liver lipid accumulation | Bhushan et al., 2019 | |
| RON | MSP global KO | Induced hepatic steatosis under normal diet, no effect on body weight | Bezerra et al., 1998 |
| RON global KO | Impaired glucose tolerance, protected from diet-induced obesity and liver steatosis | Stuart et al., 2015; Yu et al., 2016 | |
| TAM | |||
| AXL | AXL OE in myeloid cells | Increased glucose and insulin levels, increased diet-induced body weight gain | Augustine et al., 1999 |
| AXL inhibitor R428 | Reduced diet-induced body weight gain, reduced subcutaneous and gonadal fat mass | Lijnen and Christiaens, 2011 | |
| AXL global KO | No effect on body weight or fat mass | Scroyen et al., 2012 | |
| GAS6 global KO | Gained less diet-induced fat mass, protected from hepatic steatosis and fibrosis | Maquoi et al., 2005; Fourcot et al., 2011 | |
| RET | |||
| RET/GFRAL | GDF15 global OE | Decreased body and fat mass, improved glucose clearance, decreased insulin levels | Baek et al., 2006; Macia et al., 2012; Chrysovergis et al., 2014; Wang. X. et al., 2014 |
| GDF15 global KO | Increased body weight, fat mass and food intake, more prone to develop NAFLD | Tsai et al., 2013; Kim et al., 2018 | |
| GDF15 protein treatment | Decreased food intake and body weight, improved insulin sensitivity, taste aversion | Xiong et al., 2017; Chung et al., 2017; Patel et al., 2019 | |
Control of metabolism by RTKs and their ligands by using loss-or gain-of function models or by pharmacology. KO, knockout; OE, overexpression; LDL, low-density lipoprotein; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; HPA axis, hypothalamic pituitary adrenal axis.