Skip to main page content
U.S. flag
See More

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Oct 5;107(40):17391-6.
doi: 10.1073/pnas.1008025107. Epub 2010 Sep 20.

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

Teppei Fujikawa  1 , Jen-Chieh Chuang, Ichiro Sakata, Giorgio Ramadori, Roberto Coppari
Affiliations

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

Teppei Fujikawa et al. Proc Natl Acad Sci U S A. .

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Pancreatic insulin profiles in STZ-treated mice. (A) Plasma insulin and C-peptide as well as pancreatic preproinsulin mRNA and insulin levels in T1D-icv-PBS and T1D-icv-Leptin-50 mice 10 d following stereotaxic surgery and in age-matched nondiabetic control mice. (B) Representative distribution of cells expressing insulin (red) and glucagon (green) in the pancreas of mice shown in A. (Scale bar = 100 μm.) Error bars represent SEM. Statistical analyses were done using one-way ANOVA (Tukey's posttest) (n = 5–7 in each group). ***P < 0.001 vs. T1D-icv-PBS mice. ND, below the threshold of detection.
Fig. 2.
Fig. 2.
Delivery of icv leptin is restricted to the brain in STZ-induced insulin-deficient mice. Phosphorylated STAT3 (P-STAT3), STAT3, and β-actin (used as a loading control) protein levels (A) and Pomc, Npy, and Agrp mRNA contents (B) were assessed in the hypothalamus of T1D-icv-PBS and T1D-icv-Leptin-50 mice shown in Fig.1A. (C) Plasma leptin levels were measured in mice shown in Fig. 1A. (D) P-STAT3, STAT3, and β-actin (used as a loading control) protein levels were assessed in the liver of mice shown in Fig 1A. Error bars represent SEM. Statistical analyses were done using a two-tailed unpaired Student's t test or one-way ANOVA (Tukey's posttest) when two or three groups were compared, respectively (n = 5–7 in each group). *P < 0.05; **P < 0.01; ***P < 0.001 vs. T1D-icv-PBS mice. NS, not statistically different.
Fig. 3.
Fig. 3.
CNS leptin administration reverses lethality and improves diabetes in insulin-deficient mice. (A) Kaplan–Meier survival analyses were performed on T1D-icv-PBS and T1D-icv-Leptin-50 mice; the latter group had increased survival compared with the former group as determined by the Gehan–Breslow–Wilcoxon test. Mice that died during stereotaxic surgery are not included. Food intake (B), body weight (C), and blood glucose level (D) in T1D-icv-PBS and T1D-icv-Leptin-50 mice. Dashed lines represent average values measured in age-matched nondiabetic control mice. (E) Dose–response of icv leptin administration and pair-feeding effects on glycemia in T1D mice. Parameters were determined 10 d following stereotaxic surgery and in age-matched nondiabetic controls. Plasma ketone bodies, nonesterified fatty acid (NEFA), triglyceride levels and liver triglyceride contents (F), body composition (G), and glucose contents (H) in urine of T1D-icv-PBS mice, T1D-icv-Leptin-50 mice, and age-matched, nondiabetic control mice. The parameters shown in F–H were determined 10 d following stereotaxic surgery. (I) Representative photographs of cages in which T1D-icv-PBS or T1D-icv-Leptin-50 mice were housed (the bedding was unchanged for 72 h). Intensity and area of dark spots in the bedding indicate urine excretion. Error bars represent SEM (n = 3–9). Statistical analyses were done using a two-tailed unpaired Student's t test or one-way ANOVA (Tukey's posttest) when two or three groups were compared, respectively. *P < 0.05; **P < 0.01; ***P < 0.001 vs. T1D-icv-PBS mice. ND, below the threshold of detection.
Fig. 4.
Fig. 4.
CNS leptin administration improves hyperglucagonemia. Pancreatic levels of preproglucagon mRNA and glucagon levels (A); plasma glucagon contents (B); hepatic phosphoenolpyruvate carboxykinase 1 (PEPCK), glycogen synthetase 2 (GYS2), and β-actin (used as a loading control) protein levels (C); and hepatic glycogen contents (D) in T1D-icv-PBS and T1D-icv-Leptin-50 mice 10 d following stereotaxic surgery and in age-matched nondiabetic control mice. Error bars represent SEM (n = 4–7). Statistical analyses were done using one-way ANOVA (Tukey's posttest). *P < 0.05; **P < 0.01; ***P < 0.001 vs. T1D-icv-PBS mice. NS, not statistically different.
Fig. 5.
Fig. 5.
CNS leptin administration improves parameters related to glucose and fat metabolism in skeletal muscle. Glut4 and Cpt1-b mRNA levels in soleus muscle and white gastrocnemius muscle (A) and mRNA levels of glycolytic pathway enzymes in WG muscle (B) in T1D-icv-PBS and T1D-icv-Leptin-50 mice 10 d following stereotaxic surgery and in age-matched nondiabetic control mice. Error bars represent SEM (n = 4–7). Statistical analyses were done using one-way ANOVA (Tukey's posttest). *P < 0.05; **P < 0.01; ***P < 0.001 vs. T1D-icv-PBS mice.
Fig. 6.
Fig. 6.
Effects of icv leptin delivery in insulin-deficient mice quickly vanish after leptin withdrawal (WD). (A) Oral glucose tolerance test (2 g/kg of body weight) in T1D-icv-Leptin-50 mice 10 d after surgery. Glycemia levels (Left) and insulin levels (Right) in the blood. ND, below the threshold of detection. (B) Glycemia before and after icv leptin administration was interrupted in T1D-icv-Leptin-50 mice. WD1, WD2, and WD3 in the x axis indicate 1, 2, and 3 d after leptin administration was interrupted, respectively. Error bars represent SEM (n = 7).
See this image and copyright information in PMC

References

    1. Borchers AT, Uibo R, Gershwin ME. The geoepidemiology of type 1 diabetes. Autoimmun Rev. 2010;9:A355–A365. - PubMed
    1. Daneman D. Type 1 diabetes. Lancet. 2006;367:847–858. - PubMed
    1. Cryer PE. Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med. 2004;350:2272–2279. - PubMed
    1. Nathan DM, et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643–2653. - PMC - PubMed
    1. Maahs DM, Rewers M. Editorial: Mortality and renal disease in type 1 diabetes mellitus—Progress made, more to be done. J Clin Endocrinol Metab. 2006;91:3757–3759. - PubMed

Publication types

MeSH terms