Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

Teppei Fujikawa, Jen Chieh Chuang, Ichiro Sakata, Giorgio Ramadori, Roberto Coppari

Research output: Contribution to journalArticle

115 Citations (Scopus)

Abstract

Leptin monotherapy reverses the deadly consequences and improves several of the metabolic imbalances caused by insulin-deficient type 1 diabetes (T1D) in rodents. However, the mechanism(s) underlying these effects is totally unknown. Here, we report that intracerebroventricular (icv) infusion of leptin reverses lethality and greatly improves hyperglycemia, hyperglucagonemia, hyperketonemia, and polyuria caused by insulin deficiency in mice. Notably, icv leptin administration leads to increased body weight while suppressing food intake, thus correcting the catabolic consequences of T1D. Also, icv leptin delivery improves expression of the metabolically relevant hypothalamic neuropeptides proopiomelanocortin, neuropeptide Y, and agouti-related peptide in T1D mice. Furthermore, this treatment normalizes phosphoenolpyruvate carboxykinase 1 contents without affecting glycogen levels in the liver. Pancreatic β-cell regeneration does not underlie these beneficial effects of leptin, because circulating insulin levels were undetectable at basal levels and following a glucose overload. Also, pancreatic preproinsulin mRNA was completely absent in these icv leptin-treated T1D mice. Furthermore, the antidiabetic effects of icv leptin administration rapidly vanished (i.e., within 48 h) after leptin treatment was interrupted. Collectively, these results unveil a key role for the brain in mediating the antidiabetic actions of leptin in the context of T1D.

Original languageEnglish (US)
Pages (from-to)17391-17396
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number40
DOIs
StatePublished - Oct 5 2010
Externally publishedYes

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Leptin
Type 1 Diabetes Mellitus
Insulin
Therapeutics
Hypoglycemic Agents
Intraventricular Infusions
Polyuria
Pro-Opiomelanocortin
Phosphoenolpyruvate
Neuropeptide Y
Neuropeptides
Glycogen
Hyperglycemia
Regeneration
Rodentia
Eating
Body Weight
Glucose
Messenger RNA
Peptides

Keywords

  • Brain
  • Glucagon suppression
  • Glucose homeostasis
  • Leptin monotherapy

ASJC Scopus subject areas

  • General

Cite this

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. / Fujikawa, Teppei; Chuang, Jen Chieh; Sakata, Ichiro; Ramadori, Giorgio; Coppari, Roberto.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 40, 05.10.2010, p. 17391-17396.

Research output: Contribution to journalArticle

Fujikawa, Teppei ; Chuang, Jen Chieh ; Sakata, Ichiro ; Ramadori, Giorgio ; Coppari, Roberto. / Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 40. pp. 17391-17396.
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