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Characterization of Expression of Hypothalamic Appetite-Regulating Peptides in Obese Hyperleptinemic Brown Adipose Tissue-Deficient (Uncoupling Protein-Promoter-Driven Diphtheria Toxin A) Mice1
Abstract
Brown adipose tissue-deficient [uncoupling protein (UCP)-promoter-driven diphtheria toxin A (DTA)] mice develop obesity as a result of both decreased energy expenditure and hyperphagia. The hyperphagia occurs despite high serum leptin levels. Hence, this is a model of leptin-resistant obesity in which the mechanism driving hyperphagia is unknown. Leptin is a regulator of a number of hypothalamic neuropeptides involved in energy homeostasis. In ob/ob mice, leptin deficiency results in increased expression of neuropeptide Y (NPY), agouti-related protein (AGRP), and melanin-concentrating hormone (MCH), and decreased expression of POMC. We have previously shown that NPY is reduced in the UCP-DTA mouse, suggesting a normal NPY response to leptin. To define other potential sites of leptin resistance, we used in situ hybridization to evaluate the expression of messenger RNAs (mRNAs) encoding a number of peptides, including NPY, AGRP, MCH, and POMC. We confirmed that the decrease in NPY expression previously detected by Northern blots reflects a decrease in NPY expression in the arcuate nucleus. AGRP mRNA was also decreased, whereas POMC mRNA levels in the arcuate nucleus were the same as control. MCH mRNA levels in the lateral hypothalamic area were also decreased. In contrast, there was induction of NPY expression in the dorsomedial hypothalamic nucleus in the UCP-DTA animals but not in the controls. The results indicate that these neuropeptides generally respond to leptin and that the hyperphagia seen in the UCP-DTA mice is likely the result of dysregulated expression of other, as yet unexamined, hypothalamic peptides, or lies at sites distal to the hypothalamus.
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“Leptin is known to act at the hypothalamus, inhibiting the synthesis and release of orexigenic peptides, including neuropeptide Y and agoutirelated protein (21).”
From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [21]
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Metadata
- Authors
- Tritos, N. A., Elmquist, J. K., W. Mastaitis, J., Flier, J. S., & Maratos-Flier, E.
- Affiliations
- Joslin Diabetes Center (US)
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 1998-11
- Volume
- 139
- Issue
- 11
- Pages
- 4634-4641
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2100718751
- Cited by
- 82
- References
- 47
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 1 · 2020: 1 · 2018: 1 · 2016: 1 · 2015: 2 · 2014: 2 · 2013: 6 · 2012: 4
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1r29mh056537-01a1)
- National Institute of Mental Health (MH-56537)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-R37-28082, R37DK028082)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin resistance, hyperphagia, obesity, hypothalamic neuropeptides, neuropeptide Y, agouti-related protein, melanin-concentrating hormone, proopiomelanocortin, uncoupling proteins, diphtheria toxin A, arcuate nucleus, dorsomedial hypothalamus, lateral hypothalamus, energy homeostasis
- MeSH terms
- Animals, Appetite, Autoradiography, Adipose Tissue, Brown, Diphtheria Toxin, Hypothalamus, Male, Neuropeptide Y, Neuropeptides, Obesity, Pro-Opiomelanocortin, Proteins, RNA, Antisense, In Situ Hybridization, Leptin, Mice
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