Histamine regulation in glucose and lipid metabolism via histamine receptors: model for nonalcoholic steatohepatitis in mice.
Histamine has been proposed to be an important regulator of energy intake and expenditure. The aim of this study was to evaluate histamine regulation of glucose and lipid metabolism and development of nonalcoholic steatohepatitis (NASH) with a hyperlipidemic diet. Histamine regulation of glucose and lipid metabolism, adipocytokine production, and development of hyperlipidemia-induced hepatic injury were studied in histamine H1 (H1R(-/-)) and H2 (H2R(-/-)) receptor knockout and wild-type mice. H1R(-/-) mice showed mildly increased insulin resistance. In contrast, H2R(-/-) mice manifested profound insulin resistance and glucose intolerance. High-fat/high-cholesterol feeding enhanced insulin resistance and glucose intolerance. Studies with two-deoxy-2-[(18)F]-fluoro-d-glucose and positron emission tomography showed a brain glucose allocation in H1R(-/-) mice. In addition, severe NASH with hypoadiponectinemia as well as hepatic triglyceride and free cholesterol accumulation and increased blood hepatic enzymes were observed in H2R(-/-) mice. H1R(-/-) mice showed an obese phenotype with visceral adiposity, hyperleptinemia, and less severe hepatic steatosis and inflammation with increased hepatic triglyceride. These data suggest that H1R and H2R signaling may regulate glucose and lipid metabolism and development of hyperlipidemia-induced NASH.
Wang
Ke-Yong
KY
Department of Pathology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Tanimoto
Akihide
A
Yamada
Sohsuke
S
Guo
Xin
X
Ding
Yan
Y
Watanabe
Teruo
T
Watanabe
Takeshi
T
Kohno
Kimitoshi
K
Hirano
Ken-Ichi
K
Tsukada
Hideo
H
Sasaguri
Yasuyuki
Y
D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000033:anatomy & histology / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D004041:Dietary Fats / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006632:Histamine / Q000378:metabolism*; D006949:Hyperlipidemias / Q000378:metabolism; D020738:Leptin / Q000097:blood; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D019275:Radiopharmaceuticals / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000235:genetics / Q000378:metabolism*; D011970:Receptors, Histamine H2 / Q000235:genetics / Q000378:metabolism*; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism
D052242:Adiponectin; D004041:Dietary Fats; D020738:Leptin; D019275:Radiopharmaceuticals; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D051779:Sterol Regulatory Element Binding Proteins; D019788:Fluorodeoxyglucose F18; D006632:Histamine; D064429:Fatty Acid Synthases; D005947:Glucose