Chronic central leptin infusion restores hyperglycemia independent of food intake and insulin level in streptozotocin-induced diabetic rats
We examined the effects of chronic centrally administered leptin on the glucose metabolism of streptozotocin-induced diabetic (STZ-D) rats, a model for insulin-dependent diabetes mellitus. When 3 microg.rat(-1).day(-1) of leptin was infused into the third ventricle for 6 consecutive days (STZ-LEP),...
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Published in | The FASEB journal Vol. 16; no. 6; p. 509 |
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01.04.2002
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Abstract | We examined the effects of chronic centrally administered leptin on the glucose metabolism of streptozotocin-induced diabetic (STZ-D) rats, a model for insulin-dependent diabetes mellitus. When 3 microg.rat(-1).day(-1) of leptin was infused into the third ventricle for 6 consecutive days (STZ-LEP), STZ-D rats became completely euglycemic. The effect was not seen when the same dosage was administered s.c. Centrally administered leptin did not affect peripheral insulin levels. The feeding volume of STZ-LEP rats was suppressed to the level of non-STZ-D control rats. No improvement of hyperglycemia was noted when STZ-D rats were pair-fed to match the feeding volume of STZ-LEP rats. Thus, the euglycemia of STZ-LEP rats cannot be due to the decreased feeding volume. In the STZ-D rat, glucokinase mRNA, a marker of glycolysis, is down-regulated whereas glucose-6-phosphatase mRNA, a marker of gluconeogenesis, and glucose transporter (GLUT) 2, which is implicated in the release of glucose from liver, are up-regulated. GLUT4, uncoupling protein (UCP) 1, and UCP3 were down-regulated in brown adipose tissue. These parameters returned to normal upon central infusion of leptin. GLUT4 was not down-regulated in the skeletal muscle of STZ-D rats; however, fatty acid binding protein and carnitine palmitoyltransferase I, markers for utilization and beta-oxidation of fatty acids, were up-regulated and restored when the rats were treated with leptin. The increase and subsequent decrease of fatty acid utilization suggests a decrease of glucose uptake in the skeletal muscle of STZ-D rats, which was restored upon central leptin administration. We conclude that centrally infused leptin does not control serum glucose by regulating feeding volume or elevating peripheral insulin, but by regulating hepatic glucose production, peripheral glucose uptake, and energy expenditure. The present study indicates the possibility of future development of a new class of anti-diabetic agents that act centrally and independent of insulin action. |
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AbstractList | We examined the effects of chronic centrally administered leptin on the glucose metabolism of streptozotocin-induced diabetic (STZ-D) rats, a model for insulin-dependent diabetes mellitus. When 3 microg.rat(-1).day(-1) of leptin was infused into the third ventricle for 6 consecutive days (STZ-LEP), STZ-D rats became completely euglycemic. The effect was not seen when the same dosage was administered s.c. Centrally administered leptin did not affect peripheral insulin levels. The feeding volume of STZ-LEP rats was suppressed to the level of non-STZ-D control rats. No improvement of hyperglycemia was noted when STZ-D rats were pair-fed to match the feeding volume of STZ-LEP rats. Thus, the euglycemia of STZ-LEP rats cannot be due to the decreased feeding volume. In the STZ-D rat, glucokinase mRNA, a marker of glycolysis, is down-regulated whereas glucose-6-phosphatase mRNA, a marker of gluconeogenesis, and glucose transporter (GLUT) 2, which is implicated in the release of glucose from liver, are up-regulated. GLUT4, uncoupling protein (UCP) 1, and UCP3 were down-regulated in brown adipose tissue. These parameters returned to normal upon central infusion of leptin. GLUT4 was not down-regulated in the skeletal muscle of STZ-D rats; however, fatty acid binding protein and carnitine palmitoyltransferase I, markers for utilization and beta-oxidation of fatty acids, were up-regulated and restored when the rats were treated with leptin. The increase and subsequent decrease of fatty acid utilization suggests a decrease of glucose uptake in the skeletal muscle of STZ-D rats, which was restored upon central leptin administration. We conclude that centrally infused leptin does not control serum glucose by regulating feeding volume or elevating peripheral insulin, but by regulating hepatic glucose production, peripheral glucose uptake, and energy expenditure. The present study indicates the possibility of future development of a new class of anti-diabetic agents that act centrally and independent of insulin action. |
Author | Teshima, Yasushi Oka, Kyoko Noguchi, Hitoshi Okeda, Toshimitsu Yoshimatsu, Hironobu Sakata, Toshiie Kondou, Seiya Hidaka, Shuji Tsuruta, Yoshio Sakino, Hiroshi Okamoto, Kenjirou |
Author_xml | – sequence: 1 givenname: Shuji surname: Hidaka fullname: Hidaka, Shuji organization: Department of Internal Medicine I, School of Medicine, Oita Medical University, Oita, 879-5593 Japan – sequence: 2 givenname: Hironobu surname: Yoshimatsu fullname: Yoshimatsu, Hironobu – sequence: 3 givenname: Seiya surname: Kondou fullname: Kondou, Seiya – sequence: 4 givenname: Yoshio surname: Tsuruta fullname: Tsuruta, Yoshio – sequence: 5 givenname: Kyoko surname: Oka fullname: Oka, Kyoko – sequence: 6 givenname: Hitoshi surname: Noguchi fullname: Noguchi, Hitoshi – sequence: 7 givenname: Kenjirou surname: Okamoto fullname: Okamoto, Kenjirou – sequence: 8 givenname: Hiroshi surname: Sakino fullname: Sakino, Hiroshi – sequence: 9 givenname: Yasushi surname: Teshima fullname: Teshima, Yasushi – sequence: 10 givenname: Toshimitsu surname: Okeda fullname: Okeda, Toshimitsu – sequence: 11 givenname: Toshiie surname: Sakata fullname: Sakata, Toshiie |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/11919153$$D View this record in MEDLINE/PubMed |
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SubjectTerms | Animals Biomarkers - analysis Blood Glucose - analysis Diabetes Mellitus, Experimental - blood Diabetes Mellitus, Experimental - metabolism Diabetes Mellitus, Experimental - prevention & control Eating - drug effects Fatty Acids - metabolism Glucose - metabolism Hypoglycemic Agents - administration & dosage Hypoglycemic Agents - blood Hypoglycemic Agents - pharmacology Insulin - blood Leptin - administration & dosage Leptin - blood Leptin - pharmacology Liver - metabolism Male Rats Rats, Wistar RNA, Messenger - analysis Third Ventricle Up-Regulation Weight Gain |
Title | Chronic central leptin infusion restores hyperglycemia independent of food intake and insulin level in streptozotocin-induced diabetic rats |
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