leptin and 4-phenylbutyric-acid

Endoplasmic reticulum (ER) is very sensitive to the nutritional and energy states of the cells. Disruption of ER homeostasis leads to the accumulation of unfolded/misfolded proteins in the ER lumen, which is defined as ER stress. ER stress triggers the unfolded protein response (UPR). It is suggested that chronic ER stress is associated with obesity and leptin resistance. We investigated the role of ER stress and the effect of the ER stress inhibitor phenylbutyric acid (PBA) of ER stress, in obesity, as well as their impact on leptin signaling. This study involved twenty-four lean and twenty-four leptin-deficient (ob/ob) mice divided into PBA- and vehicle-treated groups. Pancreatic islets were isolated, incubated with leptin for 48 h, and assayed for the expression of CHOP and XBP1s (UPR signaling indicators) and SOCS3 (regulator of leptin signaling) by RT-qPCR. The expression levels of XBP1s and CHOP were markedly increased in the ob/ob controls compared to other groups with and without leptin treatment. No significant differences in the XBP1s and CHOP expression levels were found between the PBA-treated ob/ob and lean mice. SOCS3 expression was significantly upregulated in the PBA-treated ob/ob mice compared to the ob/ob controls after leptin treatment; but no significant difference in the SOCS3 expression was found between the PBA-treated ob/ob and lean mice with and without leptin treatment. Our findings suggested that ER stress plays an important role in the pathology of obesity, while PBA reduces ER stress and may potentially ameliorate leptin signaling.

Topics: Animals; Endoplasmic Reticulum Stress; Gene Expression Regulation; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Phenylbutyrates; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein

Leptin has not evolved as a therapeutic modality for the treatment of obesity due to the prevalence of leptin resistance in a majority of the obese population. Nevertheless, the molecular mechanisms of leptin resistance remain poorly understood. Here, we show that increased endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) in the hypothalamus of obese mice inhibits leptin receptor signaling. The genetic imposition of reduced ER capacity in mice results in severe leptin resistance and leads to a significant augmentation of obesity on a high-fat diet. Moreover, we show that chemical chaperones, 4-phenyl butyric acid (PBA), and tauroursodeoxycholic acid (TUDCA), which have the ability to decrease ER stress, act as leptin-sensitizing agents. Taken together, our results may provide the basis for a novel treatment of obesity.

Topics: Animals; Endoplasmic Reticulum; Hypothalamus; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Phenylbutyrates; Receptors, Leptin; Signal Transduction; Taurochenodeoxycholic Acid; Tunicamycin

Leptin is an important circulating signal for inhibiting food intake and body weight gain. In recent years, "leptin resistance" has been considered to be one of the main causes of obesity. However, the detailed mechanisms of leptin resistance are poorly understood. Increasing evidence has suggested that stress signals, which impair endoplasmic reticulum (ER) function, lead to an accumulation of unfolded proteins, which results in ER stress. In the present study, we hypothesized that ER stress is involved in leptin resistance. Tunicamycin, thapsigargin, or brefeldin A was used to induce ER stress. The activation status of leptin signals was measured by Western blotting analysis using a phospho-(Tyr705) signal transducer and activator of transcription 3 (STAT3) antibody. We observed that ER stress markedly inhibited leptin-induced STAT3 phosphorylation. In contrast, ER stress did not affect leptin-induced c-Jun NH(2)-terminal kinase activation. These results suggest that ER stress induces leptin resistance. ER stress-induced leptin resistance was mediated through protein tyrosine phosphatase 1B but not through suppressors of cytokine signaling 3. It is noteworthy that a chemical chaperone, which could improve the protein-folding capacity, reversed ER stress-induced leptin resistance. Moreover, homocysteine, which induces ER stress, caused leptin resistance both in vitro and in vivo. Together, these findings suggest that the pathological mechanism of leptin resistance is derived from ER stress.

Topics: Animals; Brefeldin A; Cell Line; Endoplasmic Reticulum; Homocysteine; Humans; Leptin; Mice; Mice, Inbred C57BL; Phenylbutyrates; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Receptors, Leptin; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Thapsigargin; Transfection; Tunicamycin