The deletion of glucagon-like peptide-1 receptors expressing neurons in the dorsomedial hypothalamic nucleus disrupts the diurnal feeding pattern and induces hyperphagia and obesity
Yuko Maejima | Shoko Yokota | Masaru Shimizu | Shoichiro Horita | Daisuke Kobayashi | Akihiro Hazama | Kenju Shimomura
Abstract Background Feeding rhythm disruption contributes to the development of obesity. The receptors of glucagon-like peptide-1 (GLP-1) are distributed in the wide regions of the brain. Among these regions, GLP-1 receptors (GLP-1R) are expressed in the dorsomedial hypothalamic nucleus (DMH) which are known to be associated with thermogenesis and circadian rhythm development. However, the physiological roles of GLP-1R expressing neurons in the DMH remain elusive. Methods To examine the physiological role of GLP-1R expressing neurons in the DMH, saporin-conjugated exenatide4 was injected into rat brain DMH to delete GLP-1R-positive neurons. Subsequently, locomotor activity, diurnal feeding pattern, amount of food intake and body weight were measured. Results This deletion of GLP-1R-positive neurons in the DMH induced hyperphagia, the disruption of diurnal feeding pattern, and obesity. The deletion of GLP-1R expressing neurons also reduced glutamic acid decarboxylase 67 and cholecystokinin A receptor mRNA levels in the DMH. Also, it reduced the c-fos expression after refeeding in the suprachiasmatic nucleus (SCN). Thirty percent of DMH neurons projecting to the SCN expressed GLP-1R. Functionally, refeeding after fasting induced c-fos expression in the SCN projecting neurons in the DMH. As for the projection to the DMH, neurons in the nucleus tractus solitarius (NTS) were found to be projecting to the DMH, with 33% of those neurons being GLP-1-positive. Refeeding induced c-fos expression in the DMH projecting neurons in the NTS. Conclusion These findings suggest that GLP-1R expressing neurons in the DMH may mediate feeding termination. In addition, this meal signal may be transmitted to SCN neurons and change the neural activities.
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