Recombinant methionyl human leptin administration to achieve high physiologic or pharmacologic leptin levels does not alter circulating inflammatory marker levels in humans with leptin sufficiency or excess.
Abstract
A role for high leptin levels in the proinflammatory state associated with obesity has been proposed on the basis of observational studies, but a recent interventional study employing administration of long-acting pegylated leptin resulting in very high pharmacologic levels in obese subjects did not support this idea. These interventional studies have not yet been independently confirmed, however, and varying levels and duration of hyperleptinemia as well as the presence of comorbidities such as diabetes have not yet been investigated as potential effect modifiers. We performed three interventional studies involving administration of recombinant methionyl human leptin (r-metHuLeptin) to lean, otherwise healthy obese, and obese diabetic subjects to investigate whether increasing circulating leptin levels over a wide spectrum of values (from low physiologic to high pharmacologic) would alter serum levels of inflammatory markers and other cytokines important in the T helper cell response. Increasing leptin levels from low physiologic to high physiologic in lean men and from higher physiologic to low pharmacologic in obese men over 3 d did not alter serum interferon-gamma, IL-10, TNF-alpha, monocyte chemoattractant protein-1, or soluble intercellular adhesion molecule-1. In obese subjects with type 2 diabetes mellitus, the administration of r-metHuLeptin for 4 or 16 wk, resulting in high pharmacologic leptin levels, did not activate the TNF-alpha system or increase cytokines or inflammatory markers, including IL-10, IL-6, C-reactive protein, monocyte chemoattractant protein-1, and soluble intercellular adhesion molecule-1. These findings do not support an etiopathogenic role for leptin in proinflammatory states associated with leptin excess such as obesity and have direct relevance for the potential future therapeutic use of r-metHuLeptin in humans.
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Interventional studies show a role for leptin in regulating the immune system in states of leptin deficiency, but not leptin excess as seen in obesity.
“Interventional studies investigating the effect of leptin administration to persons with leptin deficiency compared with leptin sufficiency or leptin excess could clearly show a role for leptin in regulating the immune system in states of leptin deficiency, but not leptin excess, as seen in obesity (22,27,31).”
From Leptin in humans: lessons from translational research (2009) · cites this paper as [22]
We have not found direct supporting evidence that elevated circulating leptin concentrations directly induce a state of inflammation underlying features of the metabolic syndrome in our interventional studies.
“We have not found direct supporting evidence of this hypothesis in our interventional studies (22).”
From Leptin in humans: lessons from translational research (2009) · cites this paper as [22]
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Self-citation
- Authors
- Chan, J. L., Bullen, J., Stoyneva, V., DePaoli, A. M., Addy, C., & Mantzoros, C. S.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Amgen (United States) (US)
- Corresponding author
- Mantzoros, Christos S.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2005-03-01
- Volume
- 90
- Issue
- 3
- Pages
- 1618-1624
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2158288461
- Cited by
- 60
- References
- 41
- Citations by year
- 2024: 1 · 2022: 2 · 2021: 2 · 2018: 2 · 2017: 2 · 2016: 1 · 2015: 3 · 2014: 4 · 2013: 1 · 2012: 2
- FWCI
- 6.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Amgen
- Deutsches Krebsforschungszentrum
- National Institutes of Health
- U.S. Public Health Service (R0-158785)
- National Center for Research Resources (M01-RR-01032, M01RR001032, K23RR018860)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- hyperleptinemia, obesity, type 2 diabetes, inflammation, cytokines, TNF-α, IL-10, interferon-gamma, MCP-1, soluble intercellular adhesion molecule-1, C-reactive protein, leptin therapy
- MeSH terms
- Adult, C-Reactive Protein, Humans, Insulin Resistance, Male, Obesity, Tumor Necrosis Factor-alpha, Biomarkers, Interleukin-6, Interleukin-10, Intercellular Adhesion Molecule-1, Chemokine CCL2, Leptin
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