Roles for leptin receptor/STAT3-dependent and -independent signals in the regulation of glucose homeostasis
Open accessAbstract
Leptin activates the long form of the leptin receptor (LRb) to control feeding and neuroendocrine function and thus regulate adiposity. While adiposity influences insulin sensitivity, leptin also regulates glucose homeostasis independently of energy balance. Disruption of the LRb/STAT3 signal in s/s mice results in hyperphagia, neuroendocrine dysfunction, and obesity similar to LRb null db/db mice. Insulin resistance and glucose intolerance are improved in s/s compared to db/db animals, however, suggesting that LRb/STAT3-independent signals may contribute to the regulation of glucose homeostasis by leptin. Indeed, caloric restriction normalized glycemic control in s/s animals, but db/db mice of similar weight and adiposity remained hyperglycemic. These differences in glucose homeostasis were not attributable to differences in insulin production between s/s and db/db animals but rather to decreased insulin resistance in s/s mice. Thus, in addition to LRb/STAT3-mediated adiposity signals, non-LRb/STAT3 leptin signals mediate an important adiposity-independent role in promoting glycemic control.
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The phenotype of s/s mice does not completely mimic that of ob/ob or db/db mice with respect to glucose metabolism, immune function, or reproduction, implying that other LepRb signals contribute to leptin action.
“However, the phenotype of these s/s mice does not completely mimic that of either ob/ob or db/db mice with respect to glucose metabolism, immune function or reproduction (13, 14), implying that other LepRb signals must also contribute to leptin action.”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [13]
Leptin receptor-mediated STAT3 signaling is critical for energy homeostasis but not for glucose homeostasis.
“leptin receptor-mediated STAT3 signaling appears to be critical for energy homeostasis, but not for glucose homeostasis.”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [13]
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Relevance of Serum Leptin and Leptin-Receptor Concentrations in Critically Ill Patients
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Contribution of Adipose Tissue Inflammation to the Development of Type 2 Diabetes Mellitus
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Circular RNA and Diabetes: Epigenetic Regulator with Diagnostic Role
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Self-citationPre‐ and postnatal calorie restriction perturbs early hypothalamic neuropeptide and energy balance
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Brain tumor necrosis factor-α mediates anxiety-like behavior in a mouse model of severe obesity
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LRb signals act within a distributed network of leptin‐responsive neurones to mediate leptin action
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Self-citationChanges in insulin sensitivity during leptin replacement therapy in leptin-deficient patients
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Leptin in normal physiology and leptin resistance
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Leptin signaling molecular actions and drug target in hepatocellular carcinoma
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Central signalling cross‐talk between insulin and leptin in glucose and energy homeostasis
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Obesity and Cardiometabolic Defects in Heart Failure Pathology
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Role of leptin in regulating appetite, neuroendocrine function, and bone remodeling
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Self-citationDefining the Transcriptional Targets of Leptin Reveals a Role for Atf3 in Leptin Action
Allison, M. B., Pan, W. W., MacKenzie, A., Patterson, C. M., Shah, K., Barnes, T. M., Cheng, W., Rupp, A. C., Olson, D. P., & Myers, M. G. (2018) · Diabetes · doi:10.2337/db17-1395 · Cited by 38 · see citing works
Self-citationDiabetic wound regeneration using heparin-mimetic peptide amphiphile gel in db/db mice
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Leptin Function and Regulation
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Interaction of glucose sensing and leptin action in the brain
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Molecular Approaches to Study Control of Glucose Homeostasis
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Identification of STAT target genes in adipocytes
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Hypothalamic Control of Hepatic Glucose Production and Its Potential Role in Insulin Resistance
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Self-citationEffects of Historical Differences in Components of the Japanese Diet on the Risk of Obesity in Mice
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The hypothalamic ventral premammillary nucleus: A key site in leptin's regulation of reproduction.
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Current status and patent prospective of animal models in diabetic research
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Molecular mechanisms and neural mediators of leptin actionPreprint
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Self-citationGhrelin rescues skeletal muscle catabolic profile in the R6/2 mouse model of Huntington’s disease
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The plasma 5′-AMP acts as a potential upstream regulator of hyperglycemia in type 2 diabetic mice
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The role of leptin in the regulation of neuroendocrine function and CNS development
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Self-citationAmyloid Beta Peptide Is an Endogenous Negative Allosteric Modulator of Leptin Receptor
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Past and Future of in-vitro and in-vivo Animal Models for Diabetes: A Review
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- Authors
- Bates, S. H., Kulkarni, R. N., Seifert, M., & Myers, M. G.
- Affiliations
- University of Michigan (US)
- Joslin Diabetes Center (US)
- Corresponding author
- Myers, Martin G.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2005-03
- Volume
- 1
- Issue
- 3
- Pages
- 169-178
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2122551774
- Cited by
- 173
- References
- 47
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 5 · 2022: 1 · 2021: 5 · 2020: 11 · 2019: 5 · 2018: 11 · 2017: 14 · 2016: 7 · 2015: 6 · 2014: 7 · 2013: 10 · 2012: 11
- FWCI
- 5.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (56731)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 57768, R01DK057768)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- leptin, leptin receptor, STAT3 signaling, glucose homeostasis, insulin resistance, impaired glucose tolerance, db/db mice, caloric restriction, hyperphagia, neuroendocrine dysfunction, obesity
- MeSH terms
- Animals, Body Composition, Body Weight, DNA-Binding Proteins, Glucose, Homeostasis, Hyperglycemia, Insulin Resistance, Male, Mice, Mutant Strains, Receptors, Cell Surface, Signal Transduction, Trans-Activators, Amino Acid Substitution, Caloric Restriction, STAT3 Transcription Factor, Mice, Receptors, Leptin
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