Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice.
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.
Fujikawa
Teppei
T
Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Chuang
Jen-Chieh
JC
Sakata
Ichiro
I
Ramadori
Giorgio
G
Coppari
Roberto
R
D000818:Animals; D002490:Central Nervous System / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D004195:Disease Models, Animal; D006801:Humans; D007276:Injections, Intraventricular; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D010919:Placebos; D011498:Protein Precursors / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism
D007328:Insulin; D020738:Leptin; D010919:Placebos; D011498:Protein Precursors; D054411:Receptors, Leptin; C013737:preproinsulin