Table 1.
Genetically modified mice model linking organelle stress to metabolic diseases.
| Model | Gene function | Tissue | Phenotypes |
|---|---|---|---|
| Xbp1 | UPR | Global haploinsufficiency | Weight gain, glucose intolerance, and insulin resistance on HFD [11] |
| Xbp1 | UPR | Liver-specific KO | Diminished hepatic cholesterol and triglyceride secretion and hepatic lipogenesis [22] |
| Xbp1 | UPR | Liver-specific OE | Reducing serum glucose concentrations and increasing glucose tolerance [12] Fasting and postprandial hypoglycemia; increased hepatic triglyceride content [13] |
| Xbp1 | UPR | β-cell-specific KO | Hyperglycemia and glucose intolerance resulting from decreased insulin secretion [14] |
| Perk | UPR | Mammary epithelium-specific KO | Reduced accumulation of lipid content and the milk produced [23] |
| Perk | UPR | β-cell-specific KO | Hyperglycemia associated with loss of islet and β-cell architecture [29, 30] |
| eIF2α | UPR | Phosphorylation site mutation | Defective gluconeogenesis and deficiency of pancreatic beta-cell [14] |
| Gadd34 | UPR | Liver-specific OE | Lower liver glycogen levels, fasting hypoglycemia, diminished hepatics steatosis [15] |
| Atf6 | UPR | Liver-specific OE/silencing | Increased hepatic glucose output/lowered hepatic glucose output [16] |
| Atf6 | UPR | Global KO | Hepatic steatosis [24] |
| Atf6, eIF2α, Ire1 | UPR | Global KO/phosphorylation site mutation | Hepatic steatosis [25] |
| Chop | UPR | Global KO | Delayed the onset of diabetes and beta-cell apoptosis [32] |
| Grp78 | Chaperone | Liver-specific OE | Reduced hepatic triglyceride and cholesterol contents and improved insulin sensitivity improved [17] |
| Orp150 | Chaperone | Liver-specific OE/Silencing | Improved insulin resistance and ameliorated glucose tolerance/increased insulin resistance [18] |
| Aif | Mitochondrion-localized flavoprotein | Muscle and liver-specific KO | Improved glucose tolerance, reduced fat mass, and increased insulin sensitivity [49] |
| Pgc-1α | Mitochondrial biogenesis | Global KO | Resistance to diet-induced obesity and insulin resistance [50, 51] |
| Tfam | Mitochondrial DNA transcription | Muscle-specific and adipose-specific KO | Improved glucose disposal [52, 53] |
| Tfam | Mitochondrial DNA transcription | β-cell-specific KO | Reduced β-cell mass and insulin secretion [61] |
| Cisd1 | Mitochondrial iron transport | Global and liver-specific OE | Massive expansion of adipose tissue but improved insulin sensitivity [54] |
| Fxn | Assembly of iron-sulfur cluster in mitochondria | β-cell-specific KO | Increased islet oxidative stress, reduced islet mass, and diabetes [62] |
| Atg5 | Autophagy | Adipose-specific KO | Impaired adipocyte differentiation [124] |
| Atg5 | Autophagy | Global OE | Lean, enhanced glucose tolerance, insulin sensitivity, and extended lifespan [125] |
| Atg7 | Autophagy | Global KO | Increased hepatic ER stress and impaired insulin sensitivity [69] |
| Atg7 | Autophagy | β-cell-specific KO | Reduction of β-cells mass, reduced insulin secretion, mitochondria swelling, and lower ATP production [74, 75] |
| Atg7 | Autophagy | Adipose-specific KO | Lean, browning of white adipose tissue, increased fatty acid oxidation, and improved insulin sensitivity [82, 83] |
| Atg7 | Autophagy | Muscle-specific KO | Reduced weight and body fat, enhanced glucose tolerance and insulin sensitivity, enhanced lipolysis and fatty acid oxidation, and increased FGF21 level [85] |
| Atg7 | Autophagy | AgRP neuron-specific KO | Lean with decreased food intake [126] |
| Atg7 | Autophagy | POMC neuron-specific KO | Increased body weight and food intake, impaired glucose tolerance [127, 128] |
| Atg7 | Autophagy | Myf5+ progenitors-specific KO | Impaired brown adipose tissue and skeletal muscle differentiation, browning of white adipose tissue, increased energy expenditure, increased body temperature, impaired glucose tolerance [129] |
| Atg7 | Autophagy | β-cell-specific KO in hIAPP transgenics | Decreased β-cell mass and diabetes [77–79] |
| Atg7 | Autophagy | Global haploinsufficiency in ob/ob mice | Reduces ER stress; improves insulin sensitivity and glucose tolerance ob/ob mice [84] |
| Atg7 | Autophagy | Liver-specific OE in ob/ob mice | Improved insulin sensitivity and glucose tolerance [69] |
| Atg12 | Autophagy | POMC neuron-specific KO | Weight gain, adiposity, and impaired glucose tolerance under HFD [130] |
KO: knockout; OE: overexpression; UPR: unfolded protein response; HFD: high-fat diet; AgRP: agouti-related peptide; POMC: proopiomelanocortin; hIAPP: human islet amyloid polypeptide.