Research

Decreasing mitochondrial oxidative phosphorylation (OXPHOS) coupling efficiency has been shown to be an effective therapy for obesity and related metabolic symptoms. However, the safety concerns regarding non-specific chemical uncouplers and the practical problems about the activation of natural uncoupling proteins prevent drug development in this field.

Researchers at Shanghai Institute of Materia Medica, CAS, discovered a novel cell type-specific mitochondrial uncoupler, CZ5, via screening an in-house established mitochondrial membrane potential-depolarizing compound collection.

CZ5 achieved maximal respiration in myotubes and adipocytes, whereas it did not elicit a significant increase in primary hepatocytes. In turn, CZ5 increased the ADP to ATP ratios robustly in myotubes and modestly in adipocytes but not in hepatocytes. The acute administration of CZ5 in mice increased energy expenditure.

Chronic studies in mice on high-fat diet showed that CZ5 reduced body weight and improved glucose and lipid metabolism via not only increase in energy expenditure but also suppression of energy intake. The reduced adiposity was associated with the restoration of gene expression for adipogenesis and mitochondrial biogenesis and increased genes expression for fatty acid oxidation in visceral adipose tissue. In contrast, CZ5 did not significantly affect body weight and adiposity in standard diet-fed lean mice.

This research work, performed by Ph.D candidate FU Yanyun and colleagues in LI Jia’s and Nan Fajun’s groups demonstrates that a cell type-specific mitochondrial chemical uncoupler may be potential therapeutics for high-fat diet-induced metabolic diseases and has been recently published in the journal ‘Diabetologia’. Currently, patents have been filed for the application.
Full text: http://link.springer.com/article/10.1007%2Fs00125-013-2987-9

A novel uncoupler ameliorated energy homeostasis in high-fat diet-induced obese mice via metabolic related cell-type specific OXPHOS uncoupling effects（Image by SIMM）