Mechanisms mediating renal sympathetic activation to leptin in obesity
Open accessAbstract
Leptin plays a critical role in the control of energy homeostasis. The sympathetic cardiovascular actions of leptin have emerged as a potential link between obesity and hypertension. We previously demonstrated that in mice, modest obesity induced by 10 wk of a high-fat diet is associated with preservation of leptin ability to increase renal sympathetic nerve activity (SNA) despite the resistance to the metabolic effects of leptin. Here, we examined whether selective leptin resistance exists in mice with late-stage diet-induced obesity (DIO) produced by 20 wk of a high-fat diet. The decrease in food intake and body weight induced by intraperitoneal or intracerebroventricular injection of leptin was significantly attenuated in the DIO mice. Regional SNA responses to intravenous leptin were also attenuated in DIO mice. In contrast, intracerebroventricularly administered leptin caused contrasting effects on regional SNA in DIO mice. Renal SNA response to intracerebroventricular leptin was preserved, whereas lumbar and brown adipose tissue SNA responses were attenuated. Intact renal SNA response to leptin combined with the increased cerebrospinal fluid leptin levels in DIO mice represents a potential mechanism for the adverse cardiovascular consequences of obesity. Lastly, we examined the role of phosphoinositol-3 kinase (PI3K) and melanocortin receptors (MCR) in mediating the preserved renal SNA response to leptin in obesity. Presence of PI3K inhibitor (LY294002) or MC3/4R antagonist (SHU9119) significantly attenuated the renal SNA response to leptin in DIO and agouti obese mice. Our results demonstrate the importance of PI3K and melanocortin receptors in the transduction of leptin-induced renal sympathetic activation in obesity.
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The PI3K-MC4R axis mediates the preserved renal and lumbar sympathoexcitatory effects of leptin and insulin, respectively.
“Indeed, the PI3K-MC4R axis mediates the preserved renal and lumbar sympathoexcitatory effects of leptin (52;53) and insulin (51), respectively.”
From Obesity-Associated Hypertension: Recent Progress in Deciphering the Pathogenesis (2014) · cites this paper as [52]
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- Authors
- Morgan, D. A., Thedens, D. R., Weiss, R., & Rahmouni, K.
- Affiliations
- University of Iowa (US)
- Venue
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
- Publisher
- American Physiological Society
- Published
- 2008-12
- Volume
- 295
- Issue
- 6
- Pages
- R1730-R1736
- ISSN
- 0363-6119 (ISSN-L)
- 1522-1490
- PMC
- PMC2685291
- OpenAlex
- W2062305872
- Cited by
- 89
- References
- 44
- Citations by year
- 2024: 3 · 2022: 2 · 2021: 2 · 2020: 6 · 2019: 3 · 2018: 4 · 2017: 6 · 2016: 4 · 2015: 5 · 2014: 7 · 2013: 8 · 2012: 8
- FWCI
- 4.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL-084207, P01HL084207)
- National Center for Research Resources (K26RR017369, RR017369)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Keywords
- leptin, renal sympathetic nerve activity, diet-induced obesity, leptin resistance, high-fat diet, phosphatidylinositol 3-kinase, melanocortin receptors, energy homeostasis, hypertension, brown adipose tissue, lumbar sympathetic nerve activity
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Animals, Body Weight, Adipose Tissue, Brown, Chromones, Dietary Fats, Disease Models, Animal, Dose-Response Relationship, Drug, Eating, Injections, Intraperitoneal, Injections, Intraventricular, Kidney, Lumbar Vertebrae, Male, Mice, Inbred C57BL, Mice, Obese, Morpholines, Melanocyte-Stimulating Hormones, Obesity, Sympathetic Nervous System, Time Factors, Signal Transduction, Phosphatidylinositol 3-Kinases, Leptin, Receptors, Melanocortin, Protein Kinase Inhibitors, Mice
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