Table 6.
Metabolic syndromes associated with genetic intervention of autophagy in mice.
| Setting | Genetic intervention | Effects on disease phenotype | Ref. |
|---|---|---|---|
| Diabetes | Whole‐body allelic loss of Atg7 | Development of obesity‐induced diabetes linked to augmented inflammation and lipid accumulation | Lim et al (2014) |
| Diabetes | Whole‐body deletion of Atg4b | Development of experimentally induced type I diabetes, linked to increased body weight gain upon HFD | Fernandez et al (2017) |
| Diabetes | Whole‐body knock‐in of mutant Becn1F121A | Improved insulin sensitivity, but impaired glucose tolerance upon HFD, after autophagy hyperactivation | Yamamoto et al (2018) |
| Diabetes | β cell‐specific deletion of Atg7 | Reduced glucose tolerance due to reduced β‐cell mass, and development of obesity‐induced diabetes | Ebato et al (2008), Jung et al (2008), Quan et al (2012) |
| Diabetes | shRNA‐mediated liver‐specific deletion of Atg7 | Reduced systemic glucose tolerance in obese mice linked to aberrant ER stress | Yang et al (2010) |
| NAFLD | shRNA‐mediated liver‐specific deletion of Tfeb | Increased development of severe ethanol‐induced liver injury, steatosis, and impaired lysosomal biogenesis | Chao et al (2018) |
| NAFLD | siRNA‐mediated liver‐specific deletion of Atg7 | Increased ethanol‐induced hepatocyte apoptosis and liver injury | Ding et al (2010) |
| NAFLD | Hepatocyte‐specific deletion of Rubcn | Ameliorated liver steatosis and injury upon HFD, linked to activation of lipophagy | Tanaka et al (2016) |
| NAFLD | Myeloid cell‐specific deletion of Atg5 | Enhanced toxin‐induced liver injury linked to production of pro‐inflammatory cytokines | Ilyas et al (2016) |
| NAFLD | Hepatocyte‐specific deletion of Rb1cc1 | Increased endotoxin‐induced liver injury, inflammation, and hepatic fibrosis in FILKO mice | Ma et al (2013a) |
| NAFLD / Obesity | Hepatocyte‐specific deletion of Tfeb | Increased body weight gain upon HFD due to defects in lipid degradation | Settembre et al (2013) |
| NASH | Endothelial cell‐specific deletion of Atg5 | Development of NASH and liver fibrosis, linked to enhanced inflammation | Hammoutene et al (2020) |
| Hepatic fibrosis | Hepatic stellate cell‐specific deletion of Atg7 | Reduced experimentally induced fibrogenesis and matrix accumulation in the liver | Hernandez‐Gea et al (2012) |
| Hepatic steatosis | Hepatocyte‐specific deletion of Atg7 | Marked increase in liver size, linked to increased lipid accumulation and impaired FA oxidation | Singh et al (2009a), Saito et al (2019) |
| Hepatic steatosis | Conditional hepatocyte‐specific deletion of Lamp2 | Exacerbation of liver steatosis due to impaired lipophagy and FA oxidation, after CMA inhibition | Schneider et al (2014), Kaushik and Cuervo (2015a) |
| Hepatic steatosis | Whole‐body deletion of BNip3 | Reduced β‐oxidation of fatty acids and impaired response to fasting. Elevated, inflammation, and steatohepatitis. | Glick et al (2012) |
| Hepatic steatosis | Hepatocyte‐specific deletion of Vsp15 | Exacerbation of liver steatosis due to mitochondrial depletion and impaired FA oxidation | Iershov et al (2019) |
| Hepatic steatosis | Hepatocyte‐specific deletion of Acox1 | Reduced hepatic steatosis caused by starvation or HFD after induction of autophagy | He et al (2020) |
| Metabolic syndrome | Whole‐body allelic loss of Becn2 | Increased body weight gain upon HFD, impaired glucose tolerance, and decreased insulin sensitivity | He et al (2013) |
| Metabolic syndrome | Whole‐body overexpression of Atg5 | Anti‐aging phenotypes, including leanness and increased insulin sensitivity | Pyo et al (2013) |
| Metabolic syndrome | Conditional whole‐body deletion of Acbp | Increase ability to maintain glucose levels in the normoglycemic range, by inducing lipid catabolism | Bravo‐San Pedro et al (2019) |
| Obesity | AgRP neurons‐specific deletion of Atg7 | Reduced food intake, body weight, total fat, and WAT mass | Kaushik et al (2011) |
| Obesity | Adipocyte‐specific deletion of Atg7 | Reduced body weight and WAT mass linked to enhanced insulin sensitivity and features of brown adipocytes | Singh et al (2009b), Zhang et al (2009) |
| Obesity | Adipocyte‐specific deletion of Atg5 or Atg12 | Reduced adipogenesis and body weight gain upon HFD, linked to enhanced insulin sensitivity and maintenance of beige adipocyte | Baerga et al (2009), Altshuler‐Keylin et al (2016) |
| Obesity | Whole‐body deletion of Prkn | Reduced maintenance of beige adipocyte due to mitophagy inhibition | Lu et al (2018) |
| Obesity | Conditional adipocyte‐specific deletion of Atg3 or Atg16L1 | Reduced adipose and systemic insulin resistance, linked to dysfunctional mitochondria and increased adipose tissue inflammation | Cai et al (2018) |
| Obesity | Adipocyte‐specific deletion of Rubcn | Increased systemic fat atrophy and hepatic lipid accumulation, after induction of excessive autophagy | Yamamuro et al (2020) |
AgRP, agouti‐related peptide; CMA, chaperone‐mediated autophagy; FA, fatty acid; HFD, high‐fat diet; NAFLD, non‐alcoholic fatty liver disease; NASH, non‐alcoholic steatohepatitis; WAT, white adipose tissue.