Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • It was previously proposed that

    2021-09-14

    It was previously proposed that glucagon acts in the liver, in which a signal is produced and relayed to the GSK1363089 via vagal nerves [8], [36], [37]. The concept that the liver is the primary target site was supported by the studies reporting that the glucagon receptor is localized in the liver but not vagal nerves [37]. The present study showed that the glucagon receptor is expressed in vagal afferent nerves and that glucagon-induced [Ca2+]i increases in vagal afferent NG neurons are inhibited by glucagon receptor antagonist. These results clearly demonstrate that glucagon directly interacts with the glucagon receptor to activate vagal afferent NG neurons. The function of the glucagon-activated vagal afferent NG neurons remains to be clarified. In the present study, the vagal afferent NG neurons that responded to glucagon with [Ca2+]i increases also responded to CCK and insulin. It is well known that CCK inhibits food intake by activating vagal afferent NG neurons [32], [33], [38]. We previously reported that insulin directly activates vagal afferent NG neurons and that this interaction is impaired in hyperphagic obese mice [24], suggesting that it may be involved in the anorexigenic action of insulin reported previously [12], [39], [40], [41]. Both CCK and insulin are released postprandially. Hence, it is suggested that the postprandial, transient release of glucagon, possibly in collaboration with insulin and CCK, activates NG neurons, which may be relayed to the signaling to the brain and production of satiety. The glucagon activation of NG neurons could also be implicated in the action of this hormone to stimulate energy expenditure and heat production [8], [13], [14]. Glucagon is also released under hypoglycemic conditions. Hence, the activation of NG neurons by glucagon may also be involved in the recovery from hypoglycemia, a process known to be partly regulated by brain-mediated mechanisms [3], [42]. However, further study is definitely required to clarify the physiological/pathophysiological functions of the activation of NG neurons by glucagon. The present study has demonstrated that glucagon directly interacts with vagal afferent NG neurons to induce [Ca2+]i signaling. This finding provides a clue to clarify the mechanisms for the diverse effects of glucagon, including glucose metabolism, satiety, energy expenditure and heat production.
    Acknowledgments
    This work was supported by Grant-in-Aid for Young Scientist (B) (24790221) and Scientific Research (C) (26460302) from Japan Society for the Promotion of Science (JSPS), and The Naito Foundation to YI. This work was supported by Grant-in-Aid for Scientific Research (B) (23390044) and for Challenging Exploratory Research (26670453) from JSPS, Strategic Research Program for Brain Sciences (10036069) by the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), MEXT-Supported Programs for Strategic Research Foundation at Private Universities 2011-2015 (Cooperative Basic and Clinical Research on Circadian Medicine) and 2013-2017, a Grant from Japan Diabetes Foundation, and a Grant from Salt Science Research Foundation, No. 1434 to TY. This study was subsidized by JKA through its promotion funds from KEIRIN RACE to TY.
    Introduction Glucagon receptor (GCGR) signaling helps maintain glucose homeostasis by stimulating hepatic glucose production during periods when both the influx of exogenous glucose and circulating insulin levels are low. Consistent with this, a reduction of endogenous glucagon action lowers fasting blood glucose and reduces glucose excursion during a glucose tolerance test [1], [2]. One of the more dramatic demonstrations of the impact of GCGR signaling is in rodent models of type-1 diabetes in which hyperglycemia is almost completely mitigated by deletion of Gcgr [3], [4], [5], [6], [7]. In fact, while loss of Gcgr does not prevent hyperglycemia and death under conditions of complete loss of insulin [8], [9], it is sufficient to maintain normoglycemia and promote survival under insulinopenic conditions to a degree that cannot be explained solely by the action the residual insulin [4], [7], [10].