Increased Hypothalamic Protein Tyrosine Phosphatase 1B Contributes to Leptin Resistance with Age
Open accessAbstract
Animals at advanced ages exhibit a reduction in central leptin sensitivity. However, changes in growth, metabolism, and obesity risk occur much earlier in life, particularly during the transition from youth to middle age. To determine when initial decreases in central leptin sensitivity occur, leptin-dependent suppression of food intake was tested in 8-, 12-, and 20-wk-old male, chow-fed Sprague Dawley rats. Intracerebroventricular leptin injection (3 μg) suppressed 24-h food intake in 8- and 12-wk-old rats (P < 0.05) but not 20-wk-old rats. To identify potential cellular mediators of this resistance, we focused on protein tyrosine phosphatase 1B (PTP1B), a recently described inhibitor of leptin signaling. PTP1B protein levels, as determined by Western blot, were significantly higher in mediobasal hypothalamic punches collected from 20-wk-old rats, compared with 8-wk-old rats (P < 0.05). When 20-wk-old rats were fasted for 24 h, levels of hypothalamic PTP1B decreased (P < 0.05), coincident with a restoration of leptin sensitivity. To directly test whether inhibition of PTP1B restores leptin sensitivity, 20-wk-old chow-fed rats were pretreated with a pharmacological PTP1B inhibitor 1 h before leptin, and 24-h food intake was recorded. As expected, leptin alone produced a small but nonsignificant reduction in food intake. However, pretreatment with the PTP1B inhibitor resulted in a marked improvement in leptin-dependent suppression of food intake (P < 0.05). These data are consistent with the hypothesis that increases in PTP1B contribute to hypothalamic leptin resistance as rats transition into middle age.
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High-fat feeding increases PTP1B expression in the hypothalamus.
“HF feeding increases PTP1B expression in the hypothalamus”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [120]
Pharmacological inhibition of PTP1B in the brain improves leptin sensitivity in aged-leptin resistant rats.
“pharmacological inhibition of PTP1B in the brain improves leptin sensitivity in aged-leptin resistant rats (120).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [120]
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- Authors
- Morrison, C. D., White, C. L., Wang, Z., Lee, S.-Y., Lawrence, D. S., Cefalu, W. T., Zhang, Z.-Y., & Gettys, T. W.
- Affiliations
- Pennington Biomedical Research Center (US)
- Stony Brook University (US)
- Albert Einstein College of Medicine (US)
- Indiana University Indianapolis (US)
- Corresponding author
- Morrison, Christopher D.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2007-01-01
- Volume
- 148
- Issue
- 1
- Pages
- 433-440
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC2596872
- OpenAlex
- W2133447451
- Cited by
- 106
- References
- 46
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2020: 2 · 2019: 4 · 2018: 7 · 2017: 4 · 2016: 6 · 2015: 8 · 2014: 14 · 2013: 9 · 2012: 9
- FWCI
- 2.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health
- National Institute of General Medical Sciences (P30GM118430)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK074772, DK068447, R01DK068447, R01DK074772, P30DK072476)
- National Institute of Neurological Disorders and Stroke (NS-051570, R03NS051570)
- National Center for Research Resources (P20RR021945)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin resistance, PTP1B, hypothalamus, aging, feeding inhibition, leptin signaling, PTP1B inhibitors, fasting, mediobasal hypothalamus
- MeSH terms
- Aging, Animals, Eating, Enzyme Inhibitors, Fasting, Hypothalamus, Male, Obesity, Protein Tyrosine Phosphatases, Rats, Sprague-Dawley, Leptin, Rats, Janus Kinase 2, Protein Tyrosine Phosphatase, Non-Receptor Type 1
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