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Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons.
- Source :
-
Cell metabolism [Cell Metab] 2007 Mar; Vol. 5 (3), pp. 181-94. - Publication Year :
- 2007
-
Abstract
- Despite high leptin levels, most obese humans and rodents lack responsiveness to its appetite-suppressing effects. We demonstrate that leptin modulates NPY/AgRP and alpha-MSH secretion from the ARH of lean mice. High-fat diet-induced obese (DIO) mice have normal ObRb levels and increased SOCS-3 levels, but leptin fails to modulate peptide secretion and any element of the leptin signaling cascade. Despite this leptin resistance, the melanocortin system downstream of the ARH in DIO mice is over-responsive to melanocortin agonists, probably due to upregulation of MC4R. Lastly, we show that by decreasing the fat content of the mouse's diet, leptin responsiveness of NPY/AgRP and POMC neurons recovered simultaneously, with mice regaining normal leptin sensitivity and glycemic control. These results highlight the physiological importance of leptin sensing in the melanocortin circuits and show that their loss of leptin sensing likely contributes to the pathology of leptin resistance.
- Subjects :
- Agouti-Related Protein
Animals
Arcuate Nucleus of Hypothalamus cytology
Body Composition
Diet
Dietary Fats administration & dosage
Dose-Response Relationship, Drug
Gene Expression Regulation drug effects
Hypothalamus metabolism
In Vitro Techniques
Intercellular Signaling Peptides and Proteins metabolism
Leptin administration & dosage
Male
Melanocortins metabolism
Mice
Mice, Inbred C57BL
Neuropeptide Y metabolism
Pro-Opiomelanocortin metabolism
RNA, Messenger
Signal Transduction
Weight Loss
alpha-MSH metabolism
Arcuate Nucleus of Hypothalamus metabolism
Leptin pharmacology
Neurons metabolism
Obesity metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1550-4131
- Volume :
- 5
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cell metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 17339026
- Full Text :
- https://doi.org/10.1016/j.cmet.2007.02.004