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Norepinephrine Is Required for Leptin Effects on Gene Expression in Brown and White Adipose Tissue1
Abstract
Exogenous leptin enhances energy utilization in ob/ob mice by binding its hypothalamic receptor and selectively increasing peripheral fat oxidation. Leptin also increases uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT), but the neurotransmitter that mediates this effect has not been established. The present experiments sought to determine whether leptin regulates UCP1 expression in BAT and its own expression in white adipose tissue (WAT) through the long or short forms of leptin receptor and modulation of norepinephrine release. Mice lacking dopamine beta-hydroxylase (Dbh-/-), the enzyme responsible for synthesizing norepinephrine and epinephrine from dopamine, were treated with leptin (20 microg/g body weight/day) for 3 days before they were euthanized. UCP1 messenger RNA (mRNA) and protein expression were 5-fold higher in BAT from control (Dbh+/-) compared with Dbh-/- mice. Leptin produced a 4-fold increase in UCP1 mRNA levels in Dbh+/- mice but had no effect on UCP1 expression in Dbh-/-. The beta3-adrenergic agonist, CL-316,243 increased UCP1 expression and established that BAT from both groups of mice was capable of responding to beta-adrenergic stimulation. Similarly, exogenous leptin reduced leptin mRNA in WAT from Dbh+/- but not Dbh-/- mice. In separate experiments, leptin produced comparable reductions in food intake in both Dbh+/- and Dbh-/- mice, illustrating that norepinephrine is not required for leptin's effect on food intake. Lastly, db/db mice lacking the long form of the leptin receptor failed to increase UCP1 mRNA in response to exogenous leptin but increased UCP1 mRNA in response to CL-316,243. These studies establish that norepinephrine is required for leptin to regulate its own expression in WAT and UCP1 expression in BAT and indicate that these effects are likely mediated through the centrally expressed long form of the leptin receptor.
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“In addition, leptin, released by white adipocytes, regulates energy balance by effects on the hypothalamus that lead to inhibition of food intake and increased thermogenesis via activation of the SNS, though to date there is limited evidence that leptin mediates thermogenesis via the SNS in humans 66–70.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [67]
In the citing paper
“In addition, leptin, released by white adipocytes, regulates energy balance by effects on the hypothalamus that lead to inhibition of food intake and increased thermogenesis via activation of the SNS, though to date there is limited evidence that leptin mediates thermogenesis via the SNS in humans 66–70.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [67]
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Metadata
- Authors
- Commins, S. P., Marsh, D. J., Thomas, S. A., Watson, P. M., Padgett, M. A., Palmiter, R., & Gettys, T. W.
- Affiliations
- Medical University of South Carolina (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Gettys, Thomas W.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 1999-10
- Volume
- 140
- Issue
- 10
- Pages
- 4772-4778
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2051553082
- Cited by
- 107
- References
- 52
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 4 · 2019: 5 · 2018: 3 · 2017: 4 · 2016: 2 · 2014: 3 · 2013: 7 · 2012: 2
- FWCI
- 3.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (7r01dk053981-04)
- National Institute of General Medical Sciences (GM 08716, T32GM008716)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 53981)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 09172)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin, norepinephrine, brown adipose tissue, white adipose tissue, UCP1, dopamine beta-hydroxylase, leptin receptor isoforms, beta3-adrenergic receptor, CL316,243, dietary intake, gene expression regulation, ob/ob mice, db/db mice
- MeSH terms
- Uncoupling Protein 1, Adipose Tissue, Animals, Body Weight, Adipose Tissue, Brown, Carrier Proteins, Diabetes Mellitus, Dopamine beta-Hydroxylase, Eating, Ion Channels, Male, Membrane Proteins, Mice, Inbred C57BL, Norepinephrine, Proteins, RNA, Messenger, Gene Expression, Mice, Knockout, Leptin, Mitochondrial Proteins, Mice
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