Nighttime Administration of Nicotine Improves Hepatic Glucose Metabolism via the Hypothalamic Orexin System in Mice.
Nicotine is known to affect the metabolism of glucose; however, the underlying mechanism remains unclear. Therefore, we here investigated whether nicotine promoted the central regulation of glucose metabolism, which is closely linked to the circadian system. The oral intake of nicotine in drinking water, which mainly occurred during the nighttime active period, enhanced daily hypothalamic prepro-orexin gene expression and reduced hyperglycemia in type 2 diabetic db/db mice without affecting body weight, body fat content, and serum levels of insulin. Nicotine administered at the active period appears to be responsible for the effect on blood glucose, because nighttime but not daytime injections of nicotine lowered blood glucose levels in db/db mice. The chronic oral treatment with nicotine suppressed the mRNA levels of glucose-6-phosphatase, the rate-limiting enzyme of gluconeogenesis, in the liver of db/db and wild-type control mice. In the pyruvate tolerance test to evaluate hepatic gluconeogenic activity, the oral nicotine treatment moderately suppressed glucose elevations in normal mice and mice lacking dopamine receptors, whereas this effect was abolished in orexin-deficient mice and hepatic parasympathectomized mice. Under high-fat diet conditions, the oral intake of nicotine lowered blood glucose levels at the daytime resting period in wild-type, but not orexin-deficient, mice. These results indicated that the chronic daily administration of nicotine suppressed hepatic gluconeogenesis via the hypothalamic orexin-parasympathetic nervous system. Thus, the results of the present study may provide an insight into novel chronotherapy for type 2 diabetes that targets the central cholinergic and orexinergic systems.
Department of Clinical Pharmacology (H.T., T.N., M.F., K.K., N.W., M.T., K.Y., T.W., T.Sas.) and System Emotional Science (H.N.), University of Toyama, Toyama 930-0194, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Y.), University of Tsukuba, Tsukuba 305-8575, Japan; Department of Molecular Genetics (M.Y.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Department of Molecular Neuroscience and Integrative Physiology (T.Sak.), Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
Hiroshi
H
Tsuneki
Department of Clinical Pharmacology (H.T., T.N., M.F., K.K., N.W., M.T., K.Y., T.W., T.Sas.) and System Emotional Science (H.N.), University of Toyama, Toyama 930-0194, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Y.), University of Tsukuba, Tsukuba 305-8575, Japan; Department of Molecular Genetics (M.Y.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Department of Molecular Neuroscience and Integrative Physiology (T.Sak.), Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
Takashi
T
Nagata
Department of Clinical Pharmacology (H.T., T.N., M.F., K.K., N.W., M.T., K.Y., T.W., T.Sas.) and System Emotional Science (H.N.), University of Toyama, Toyama 930-0194, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Y.), University of Tsukuba, Tsukuba 305-8575, Japan; Department of Molecular Genetics (M.Y.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Department of Molecular Neuroscience and Integrative Physiology (T.Sak.), Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
Mikio
M
Fujita
Department of Clinical Pharmacology (H.T., T.N., M.F., K.K., N.W., M.T., K.Y., T.W., T.Sas.) and System Emotional Science (H.N.), University of Toyama, Toyama 930-0194, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Y.), University of Tsukuba, Tsukuba 305-8575, Japan; Department of Molecular Genetics (M.Y.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Department of Molecular Neuroscience and Integrative Physiology (T.Sak.), Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
Kanta
K
Kon
Department of Clinical Pharmacology (H.T., T.N., M.F., K.K., N.W., M.T., K.Y., T.W., T.Sas.) and System Emotional Science (H.N.), University of Toyama, Toyama 930-0194, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Y.), University of Tsukuba, Tsukuba 305-8575, Japan; Department of Molecular Genetics (M.Y.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Department of Molecular Neuroscience and Integrative Physiology (T.Sak.), Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
Naizhen
N
Wu
Department of Clinical Pharmacology (H.T., T.N., M.F., K.K., N.W., M.T., K.Y., T.W., T.Sas.) and System Emotional Science (H.N.), University of Toyama, Toyama 930-0194, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Y.), University of Tsukuba, Tsukuba 305-8575, Japan; Department of Molecular Genetics (M.Y.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Department of Molecular Neuroscience and Integrative Physiology (T.Sak.), Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
Mayumi
M
Takatsuki
Department of Clinical Pharmacology (H.T., T.N., M.F., K.K., N.W., M.T., K.Y., T.W., T.Sas.) and System Emotional Science (H.N.), University of Toyama, Toyama 930-0194, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Y.), University of Tsukuba, Tsukuba 305-8575, Japan; Department of Molecular Genetics (M.Y.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Department of Molecular Neuroscience and Integrative Physiology (T.Sak.), Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
Kaoru
K
Yamaguchi
Department of Clinical Pharmacology (H.T., T.N., M.F., K.K., N.W., M.T., K.Y., T.W., T.Sas.) and System Emotional Science (H.N.), University of Toyama, Toyama 930-0194, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Y.), University of Tsukuba, Tsukuba 305-8575, Japan; Department of Molecular Genetics (M.Y.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Department of Molecular Neuroscience and Integrative Physiology (T.Sak.), Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
Tsutomu
T
Wada
Department of Clinical Pharmacology (H.T., T.N., M.F., K.K., N.W., M.T., K.Y., T.W., T.Sas.) and System Emotional Science (H.N.), University of Toyama, Toyama 930-0194, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Y.), University of Tsukuba, Tsukuba 305-8575, Japan; Department of Molecular Genetics (M.Y.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Department of Molecular Neuroscience and Integrative Physiology (T.Sak.), Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
Hisao
H
Nishijo
Department of Clinical Pharmacology (H.T., T.N., M.F., K.K., N.W., M.T., K.Y., T.W., T.Sas.) and System Emotional Science (H.N.), University of Toyama, Toyama 930-0194, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Y.), University of Tsukuba, Tsukuba 305-8575, Japan; Department of Molecular Genetics (M.Y.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Department of Molecular Neuroscience and Integrative Physiology (T.Sak.), Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
Masashi
M
Yanagisawa
Department of Clinical Pharmacology (H.T., T.N., M.F., K.K., N.W., M.T., K.Y., T.W., T.Sas.) and System Emotional Science (H.N.), University of Toyama, Toyama 930-0194, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Y.), University of Tsukuba, Tsukuba 305-8575, Japan; Department of Molecular Genetics (M.Y.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Department of Molecular Neuroscience and Integrative Physiology (T.Sak.), Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
Takeshi
T
Sakurai
Department of Clinical Pharmacology (H.T., T.N., M.F., K.K., N.W., M.T., K.Y., T.W., T.Sas.) and System Emotional Science (H.N.), University of Toyama, Toyama 930-0194, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS) (M.Y.), University of Tsukuba, Tsukuba 305-8575, Japan; Department of Molecular Genetics (M.Y.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Department of Molecular Neuroscience and Integrative Physiology (T.Sak.), Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
Toshiyasu
T
Sasaoka
D000818:Animals; D003433:Crosses, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D055870:Drug Chronotherapy; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects*; D006943:Hyperglycemia / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009538:Nicotine / Q000008:administration & dosage* / Q000627:therapeutic use; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000627:therapeutic use; D009765:Obesity / Q000150:complications / Q000209:etiology; D000068797:Orexins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism
C000600618:DRD2 protein, mouse; C583261:Drd1 protein, mouse; C000596233:Hcrt protein, mouse; D007004:Hypoglycemic Agents; D018722:Nicotinic Agonists; D000068797:Orexins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D009538:Nicotine