A major role for perifornical orexin neurons in the control of glucose metabolism in rats

C.X. Yi, M.J. Serlie, M.T. Ackermans, E. Foppen, R.M. Buijs, H.P. Sauerwein, E. Fliers, A. Kalsbeek

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    Abstract

    OBJECTIVE: The hypothalamic neuropeptide orexin influences (feeding) behavior as well as energy metabolism. Administration of exogenous orexin-A into the brain has been shown to increase both food intake and blood glucose levels. In the present study, we investigated the role of endogenous hypothalamic orexin release in glucose homeostasis in rats. RESEARCH DESIGN AND METHODS: We investigated the effects of the hypothalamic orexin system on basal endogenous glucose production (EGP) as well as on hepatic and peripheral insulin sensitivity by changing orexinergic activity in the hypothalamus combined with hepatic sympathetic or parasympathetic denervation, two-step hyperinsulinemic-euglycemic clamps, immunohistochemistry, and RT-PCR studies. RESULTS: Hypothalamic disinhibition of neuronal activity by the gamma-aminobutyric acid receptor antagonist bicuculline (BIC) increased basal EGP, especially when BIC was administered in the perifornical area where orexin-containing neurons but not melanocortin-concentrating hormone-containing neurons were activated. The increased BIC-induced EGP was largely prevented by intracerebroventricular pretreatment with the orexin-1 receptor antagonist. Intracerebroventricular administration of orexin-A itself caused an increase in plasma glucose and prevented the daytime decrease of EGP. The stimulatory effect of intracerebroventricular orexin-A on EGP was prevented by hepatic sympathetic denervation. Plasma insulin clamped at two or six times the basal levels did not counteract the stimulatory effect of perifornical BIC on EGP, indicating hepatic insulin resistance. RT-PCR showed that stimulation of orexin neurons increased the expression of hepatic glucoregulatory enzymes. CONCLUSIONS: Hypothalamic orexin plays an important role in EGP, most likely by changing the hypothalamic output to the autonomic nervous system. Disturbance of this pathway may result in unbalanced glucose homeostasis.
    Original languageEnglish
    Pages (from-to)1998-2005
    JournalDiabetes
    Volume58
    Issue number9
    DOIs
    Publication statusPublished - 1 Jan 2009

    Cite this

    Yi, C. X., Serlie, M. J., Ackermans, M. T., Foppen, E., Buijs, R. M., Sauerwein, H. P., ... Kalsbeek, A. (2009). A major role for perifornical orexin neurons in the control of glucose metabolism in rats. Diabetes, 58(9), 1998-2005. https://doi.org/10.2337/db09-0385
    Yi, C.X. ; Serlie, M.J. ; Ackermans, M.T. ; Foppen, E. ; Buijs, R.M. ; Sauerwein, H.P. ; Fliers, E. ; Kalsbeek, A. / A major role for perifornical orexin neurons in the control of glucose metabolism in rats. In: Diabetes. 2009 ; Vol. 58, No. 9. pp. 1998-2005.
    @article{27f1532b3cf24600ac13b7db6677de3a,
    title = "A major role for perifornical orexin neurons in the control of glucose metabolism in rats",
    abstract = "OBJECTIVE: The hypothalamic neuropeptide orexin influences (feeding) behavior as well as energy metabolism. Administration of exogenous orexin-A into the brain has been shown to increase both food intake and blood glucose levels. In the present study, we investigated the role of endogenous hypothalamic orexin release in glucose homeostasis in rats. RESEARCH DESIGN AND METHODS: We investigated the effects of the hypothalamic orexin system on basal endogenous glucose production (EGP) as well as on hepatic and peripheral insulin sensitivity by changing orexinergic activity in the hypothalamus combined with hepatic sympathetic or parasympathetic denervation, two-step hyperinsulinemic-euglycemic clamps, immunohistochemistry, and RT-PCR studies. RESULTS: Hypothalamic disinhibition of neuronal activity by the gamma-aminobutyric acid receptor antagonist bicuculline (BIC) increased basal EGP, especially when BIC was administered in the perifornical area where orexin-containing neurons but not melanocortin-concentrating hormone-containing neurons were activated. The increased BIC-induced EGP was largely prevented by intracerebroventricular pretreatment with the orexin-1 receptor antagonist. Intracerebroventricular administration of orexin-A itself caused an increase in plasma glucose and prevented the daytime decrease of EGP. The stimulatory effect of intracerebroventricular orexin-A on EGP was prevented by hepatic sympathetic denervation. Plasma insulin clamped at two or six times the basal levels did not counteract the stimulatory effect of perifornical BIC on EGP, indicating hepatic insulin resistance. RT-PCR showed that stimulation of orexin neurons increased the expression of hepatic glucoregulatory enzymes. CONCLUSIONS: Hypothalamic orexin plays an important role in EGP, most likely by changing the hypothalamic output to the autonomic nervous system. Disturbance of this pathway may result in unbalanced glucose homeostasis.",
    author = "C.X. Yi and M.J. Serlie and M.T. Ackermans and E. Foppen and R.M. Buijs and H.P. Sauerwein and E. Fliers and A. Kalsbeek",
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    Yi, CX, Serlie, MJ, Ackermans, MT, Foppen, E, Buijs, RM, Sauerwein, HP, Fliers, E & Kalsbeek, A 2009, 'A major role for perifornical orexin neurons in the control of glucose metabolism in rats', Diabetes, vol. 58, no. 9, pp. 1998-2005. https://doi.org/10.2337/db09-0385

    A major role for perifornical orexin neurons in the control of glucose metabolism in rats. / Yi, C.X.; Serlie, M.J.; Ackermans, M.T.; Foppen, E.; Buijs, R.M.; Sauerwein, H.P.; Fliers, E.; Kalsbeek, A.

    In: Diabetes, Vol. 58, No. 9, 01.01.2009, p. 1998-2005.

    Research output: Contribution to journalArticleAcademicpeer-review

    TY - JOUR

    T1 - A major role for perifornical orexin neurons in the control of glucose metabolism in rats

    AU - Yi, C.X.

    AU - Serlie, M.J.

    AU - Ackermans, M.T.

    AU - Foppen, E.

    AU - Buijs, R.M.

    AU - Sauerwein, H.P.

    AU - Fliers, E.

    AU - Kalsbeek, A.

    PY - 2009/1/1

    Y1 - 2009/1/1

    N2 - OBJECTIVE: The hypothalamic neuropeptide orexin influences (feeding) behavior as well as energy metabolism. Administration of exogenous orexin-A into the brain has been shown to increase both food intake and blood glucose levels. In the present study, we investigated the role of endogenous hypothalamic orexin release in glucose homeostasis in rats. RESEARCH DESIGN AND METHODS: We investigated the effects of the hypothalamic orexin system on basal endogenous glucose production (EGP) as well as on hepatic and peripheral insulin sensitivity by changing orexinergic activity in the hypothalamus combined with hepatic sympathetic or parasympathetic denervation, two-step hyperinsulinemic-euglycemic clamps, immunohistochemistry, and RT-PCR studies. RESULTS: Hypothalamic disinhibition of neuronal activity by the gamma-aminobutyric acid receptor antagonist bicuculline (BIC) increased basal EGP, especially when BIC was administered in the perifornical area where orexin-containing neurons but not melanocortin-concentrating hormone-containing neurons were activated. The increased BIC-induced EGP was largely prevented by intracerebroventricular pretreatment with the orexin-1 receptor antagonist. Intracerebroventricular administration of orexin-A itself caused an increase in plasma glucose and prevented the daytime decrease of EGP. The stimulatory effect of intracerebroventricular orexin-A on EGP was prevented by hepatic sympathetic denervation. Plasma insulin clamped at two or six times the basal levels did not counteract the stimulatory effect of perifornical BIC on EGP, indicating hepatic insulin resistance. RT-PCR showed that stimulation of orexin neurons increased the expression of hepatic glucoregulatory enzymes. CONCLUSIONS: Hypothalamic orexin plays an important role in EGP, most likely by changing the hypothalamic output to the autonomic nervous system. Disturbance of this pathway may result in unbalanced glucose homeostasis.

    AB - OBJECTIVE: The hypothalamic neuropeptide orexin influences (feeding) behavior as well as energy metabolism. Administration of exogenous orexin-A into the brain has been shown to increase both food intake and blood glucose levels. In the present study, we investigated the role of endogenous hypothalamic orexin release in glucose homeostasis in rats. RESEARCH DESIGN AND METHODS: We investigated the effects of the hypothalamic orexin system on basal endogenous glucose production (EGP) as well as on hepatic and peripheral insulin sensitivity by changing orexinergic activity in the hypothalamus combined with hepatic sympathetic or parasympathetic denervation, two-step hyperinsulinemic-euglycemic clamps, immunohistochemistry, and RT-PCR studies. RESULTS: Hypothalamic disinhibition of neuronal activity by the gamma-aminobutyric acid receptor antagonist bicuculline (BIC) increased basal EGP, especially when BIC was administered in the perifornical area where orexin-containing neurons but not melanocortin-concentrating hormone-containing neurons were activated. The increased BIC-induced EGP was largely prevented by intracerebroventricular pretreatment with the orexin-1 receptor antagonist. Intracerebroventricular administration of orexin-A itself caused an increase in plasma glucose and prevented the daytime decrease of EGP. The stimulatory effect of intracerebroventricular orexin-A on EGP was prevented by hepatic sympathetic denervation. Plasma insulin clamped at two or six times the basal levels did not counteract the stimulatory effect of perifornical BIC on EGP, indicating hepatic insulin resistance. RT-PCR showed that stimulation of orexin neurons increased the expression of hepatic glucoregulatory enzymes. CONCLUSIONS: Hypothalamic orexin plays an important role in EGP, most likely by changing the hypothalamic output to the autonomic nervous system. Disturbance of this pathway may result in unbalanced glucose homeostasis.

    U2 - 10.2337/db09-0385

    DO - 10.2337/db09-0385

    M3 - Article

    VL - 58

    SP - 1998

    EP - 2005

    JO - Diabetes

    JF - Diabetes

    SN - 0012-1797

    IS - 9

    ER -

    Yi CX, Serlie MJ, Ackermans MT, Foppen E, Buijs RM, Sauerwein HP et al. A major role for perifornical orexin neurons in the control of glucose metabolism in rats. Diabetes. 2009 Jan 1;58(9):1998-2005. https://doi.org/10.2337/db09-0385