Researchers Suggest Role for Hypothalamic PPAR-Gamma in Diabetes Drug-Related Weight Gain

Two separate research teams claim that activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) in the brain plays a role in the mechanisms that cause weight gain among patients receiving thiazolidinedione (TZD) treatment for type 2 diabetes. The two sets of animal-based research, one led by a team at the University of California, San Diego (UCSD), and the other carried out by scientists at the University of Cincinnati College of Medicine, have identified a previously unknown role for central nervous system PPAR-γ in the regulation of energy balance, leptin sensitivity, and at least some of the weight gain associated with administering PPAR-γ–modulating drugs. Both research teams published their results in Nature Medicine...

To investigate this possibility further, Jerrold M. Olefsky, Ph.D., at UCSD’s Department of Medicine, and colleagues, generated mice in which the gene for PPAR-γ was knocked out only in the brain (Pparg brain knockout [BKO] mice), to determine whether neuronal PPAR-γ signalling contributes to either weight gain or insulin sensitivity...

Studies by Dr. Seeley’s team also concurred with those of the UCSD team with regard to the effects of CNS PPAR-γ on leptin signalling. Leptin sig­nalling in the hypothalamus is blunted in rats fed a HFD, and this leptin resistance is thought to contribute to the continued accumu­lation of body fat. The Cincinnati team hypothesized that hypothalamic PPAR-γ specifically may contribute to the development of HFD-induced leptin resistance, and that chronic antagonism of CNS PPAR-γ would restore leptin sensitivity these animals. To test this, they administered the PPAR-γ antagonist into the lateral ventricle of HFD-fed rats, at a dose that had no effect on body weight but that did result in significantly lower hypothalamic expression of PPAR-γ’s target gene lipoprotein lipase...