Abstract
BackgroundFeeding 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.MethodsTo 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.ResultsThis 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.ConclusionThese 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.
Highlights
Feeding rhythm disruption contributes to the development of obesity
M The scheme of the role of GLP-1 receptors (GLP-1R) expressing neurons in the dorsomedial hypothalamic nucleus (DMH). “meal” signal may be transmitted to suprachiasmatic nucleus (SCN) neurons and change the neural activities partially via nucleus tractus solitarius (NTS) glucagon-like peptide-1 (GLP-1) neurons and DMH GLP-1R expressing neurons in the NTS-containing sections from rats with Cholera toxin subunit B (CTB) injected into the DMH (Fig. 4A)
Because there are very few reports regarding the contribution of DMH neurons on meal-oriented circadian rhythm regulation, we focused on the upstream of the DMH
Summary
To examine the physiological role of GLP-1R expressing neurons in the DMH, saporin-conjugated exenatide was injected into rat brain DMH to delete GLP-1R-positive neurons. Locomotor activity, diurnal feeding pattern, amount of food intake and body weight were measured. Animals and housing Male Wistar rats (9 weeks old) were purchased from Japan SLC. The animals were maintained on a 12-h light/ dark cycle and given conventional food (CE-2; Clea, Osaka, Japan) and water ad libitum. In all the experiments measuring the food intake and body weight in more than two groups, initial body weight of different groups were matched prior to the start to the experiments. After 2 h of refeeding, the rats were injected with a mixture of three types of anaesthetic agents [(0.003%, Domitor, Nippon Zenyaku Kogyo Co., Ltd., Koriyama, Japan), midazolam (0.04%, Dormicum, Astellas Pharma Inc., Tokyo, Japan), and butorphanol tartrate (0.05%, Vetorphale, Meiji Seika Pharma Co., Ltd., Tokyo, Japan)] (5 ml/kg) and perfused intracardially with 4% paraformaldehyde (PFA), and 0.2% picric acid
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