taurochenodeoxycholic-acid and Hyperphagia

Obesity is associated with the activation of cellular responses, such as endoplasmic reticulum (ER) stress. Here, we show that leptin-deficient ob/ob mice display elevated hypothalamic ER stress as early as postnatal day 10, i.e., prior to the development of obesity in this mouse model. Neonatal treatment of ob/ob mice with the ER stress-relieving drug tauroursodeoxycholic acid (TUDCA) causes long-term amelioration of body weight, food intake, glucose homeostasis, and pro-opiomelanocortin (POMC) projections. Cells exposed to ER stress often activate autophagy. Accordingly, we report that in vitro induction of ER stress and neonatal leptin deficiency in vivo activate hypothalamic autophagy-related genes. Furthermore, genetic deletion of autophagy in pro-opiomelanocortin neurons of ob/ob mice worsens their glucose homeostasis, adiposity, hyperphagia, and POMC neuronal projections, all of which are ameliorated with neonatal TUDCA treatment. Together, our data highlight the importance of early life ER stress-autophagy pathway in influencing hypothalamic circuits and metabolic regulation.

Topics: Adiposity; Animals; Antiviral Agents; Autophagy; Autophagy-Related Protein 7; Body Weight; Cholagogues and Choleretics; Disease Models, Animal; Eating; Endoplasmic Reticulum Stress; Energy Metabolism; Feeding Behavior; Homeostasis; Hyperphagia; Hypothalamus; Leptin; Male; Metabolic Diseases; Mice; Mice, Inbred Strains; Mice, Knockout; Neuroendocrinology; Neurogenesis; Obesity; Pro-Opiomelanocortin; Taurochenodeoxycholic Acid

Sleep fragmentation (SF) is highly prevalent and may constitute an important contributing factor to excessive weight gain and the metabolic syndrome. Increased endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) leading to the attenuation of leptin receptor signaling in the hypothalamus leads to obesity and metabolic dysfunction.. Mice were exposed to SF and sleep control (SC) for varying periods of time during which ingestive behaviors were monitored. UPR pathways and leptin receptor signaling were assessed in hypothalami. To further examine the mechanistic role of ER stress, changes in leptin receptor (ObR) signaling were also examined in wild-type mice treated with the ER chaperone tauroursodeoxycholic acid (TUDCA), as well as in CHOP-/+ transgenic mice.. Fragmented sleep in male mice induced increased food intake starting day 3 and thereafter, which was preceded by increases in ER stress and activation of all three UPR pathways in the hypothalamus. Although ObR expression was unchanged, signal transducer and activator of transcription 3 (STAT3) phosphorylation was decreased, suggesting reduced ObR signaling. Unchanged suppressor of cytokine signaling-3 (SOCS3) expression and increases in protein-tyrosine phosphatase 1B (PTP1B) expression and activity emerged with SF, along with reduced p-STAT3 responses to exogenous leptin. SF-induced effects were reversed following TUDCA treatment and were absent in CHOP -/+ mice.. SF induces hyperphagic behaviors and reduced leptin signaling in hypothalamus that are mediated by activation of ER stress, and ultimately lead to increased PTP1B activity. ER stress pathways are therefore potentially implicated in SF-induced weight gain and metabolic dysfunction, and may represent a viable therapeutic target.

Topics: Animals; Eating; Endoplasmic Reticulum Stress; Heterozygote; Hyperphagia; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Receptors, Leptin; Signal Transduction; Sleep; Sleep Deprivation; STAT3 Transcription Factor; Taurochenodeoxycholic Acid; Transcription Factor CHOP; Unfolded Protein Response