Diabetes Metab J.  2012 Aug;36(4):293-299. 10.4093/dmj.2012.36.4.293.

Intracerebroventricular Injection of Metformin Induces Anorexia in Rats

• Lee CK
• Choi YJ
• Park SY
• Kim JY
• Won KC
• Kim YW

• KMID: 2174427
• DOI: http://doi.org/10.4093/dmj.2012.36.4.293

Abstract

BACKGROUND
Metformin, an oral biguanide insulin-sensitizing agent, is well known to decrease appetite. Although there is evidence that metformin could affect the brain directly, the exact mechanism is not yet known.
METHODS
To evaluate whether metformin induces anorexia via the hypothalamus, various concentrations of metformin were injected into the lateral ventricle of rats through a chronically implanted catheter and food intake was measured for 24 hours. The hypothalamic neuropeptides associated with regulation of food intake were also analyzed following 1 hour of intracerebroventricular (ICV) injections of metformin.
RESULTS
An ICV injection of metformin decreased food intake in a dose-dependent manner in unrestrained conscious rats. Hypothalamic phosphorylated AMP-activated protein kinase (pAMPK) increased by 3 microg with metformin treatment, but there was no further increase in pAMPK with increases in metformin dosage. The hypothalamic phosphorylated signal transducer and activator of transcription 3 (pSTAT3) increased by 3 microg with metformin treatment, but, there was no further increase in pSTAT3 level following increases of metformin dosage. Hypothalamic proopiomelanocortin was elevated with metformin treatment, while neuropeptide Y was not significantly changed.
CONCLUSION
Our results suggest that metformin induces anorexia via direct action in the hypothalamus and the increase in pSTAT3, at least in part, is involved in the process. However, hypothalamic pAMPK appears not to contribute to metformin-induced appetite reduction in normal rats. Further studies exploring new pathways connecting metformin and feeding regulation are needed.

Keyword

Appetite; Hypothalamus; Metformin; Pro-opiomelanocortin

MeSH Terms

AMP-Activated Protein Kinases
Animals
Anorexia
Appetite
Brain
Catheters
Eating
Hypothalamus
Lateral Ventricles
Metformin
Neuropeptide Y
Neuropeptides
Pro-Opiomelanocortin
Rats
STAT3 Transcription Factor
AMP-Activated Protein Kinases
Metformin
Neuropeptide Y
Neuropeptides
Pro-Opiomelanocortin
STAT3 Transcription Factor

Figure

• 

  Fig. 1 Cumulative food intake following injection of various dosages of metformin into the lateral ventricle through a chronically implanted catheter in conscious unrestrained rats. Values are presented as mean±standard error. The cumulative food intake following metformin injection decreased in a dose-dependent manner analyzed by the P trend test with ANOVA (P trend <0.05).

• 

  Fig. 2 The hypothalamic levels of phosphorylated AMP-activated protein (pAMPK) and phosphorylated signal transducer, activator of transcription 3 (pSTAT3), and phosphoinositide-3-kinase (PI3K) following intracerebroventricular injection of metformin. Representative blots are shown in (A) and the densitometric data are denoted in (B), (C), and (D). Values are presented as mean±standard error of 6, 5, 4, and 6 in 0, 3, 30, or 300 µg of metformin-treated rats, respectively. Values that do not share a common superscript are significantly different at P<0.05.

• 

  Fig. 3 Expression of proopiomelanocortin (POMC) (A) and neuropeptide Y (NPY) (B) in the hypothalamus following intracerebroventricular injection of metformin. Expression was measured by real-time polymerase chain reaction. Bars are mean±standard error. The number of cases are 6, 5, 4, and 6 in 0, 3, 30, or 300 µg of metformin-treated rats, respectively. Values that do not share a common superscript are significantly different at P<0.05.

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