First Author | Lu B | Year | 2014 |
Journal | Diabetes | Volume | 63 |
Issue | 9 | Pages | 2935-48 |
PubMed ID | 24722244 | Mgi Jnum | J:229878 |
Mgi Id | MGI:5754709 | Doi | 10.2337/db13-1531 |
Citation | Lu B, et al. (2014) Metabolic crosstalk: molecular links between glycogen and lipid metabolism in obesity. Diabetes 63(9):2935-48 |
abstractText | Glycogen and lipids are major storage forms of energy that are tightly regulated by hormones and metabolic signals. We demonstrate that feeding mice a high-fat diet (HFD) increases hepatic glycogen due to increased expression of the glycogenic scaffolding protein PTG/R5. PTG promoter activity was increased and glycogen levels were augmented in mice and cells after activation of the mechanistic target of rapamycin complex 1 (mTORC1) and its downstream target SREBP1. Deletion of the PTG gene in mice prevented HFD-induced hepatic glycogen accumulation. Of note, PTG deletion also blocked hepatic steatosis in HFD-fed mice and reduced the expression of numerous lipogenic genes. Additionally, PTG deletion reduced fasting glucose and insulin levels in obese mice while improving insulin sensitivity, a result of reduced hepatic glucose output. This metabolic crosstalk was due to decreased mTORC1 and SREBP activity in PTG knockout mice or knockdown cells, suggesting a positive feedback loop in which once accumulated, glycogen stimulates the mTORC1/SREBP1 pathway to shift energy storage to lipogenesis. Together, these data reveal a previously unappreciated broad role for glycogen in the control of energy homeostasis. |