The DOI matches its Crossref record; 61 of the 61 references it cites were found in a registry or an index.
Region-Specific Leptin Resistance within the Hypothalamus of Diet-Induced Obese Mice
Abstract
Leptin resistance in diet-induced obese (DIO) mice is characterized by elevated serum leptin and a decreased response to exogenous leptin and is caused by unknown defects in the central nervous system. Leptin normally acts on several brain nuclei, but a detailed description of leptin resistance within individual brain regions has not been reported. We first mapped leptin-responsive cells in brains from DIO mice using phospho-signal transducer and activator of transcription (P-STAT3) immunohistochemistry. After 16 wk of high-fat-diet feeding, leptin-activated P-STAT3 staining within the arcuate nucleus (ARC) was dramatically decreased. In contrast, other hypothalamic and extrahypothalamic nuclei remained leptin sensitive. Reduced leptin-induced P-STAT3 in the ARC could also be detected after 4 wk and as early as 6 d of a high-fat diet. To examine potential mechanisms for leptin-resistant STAT3 activation in the ARC of DIO mice, we measured mRNA levels of candidate signaling molecules in the leptin receptor-STAT3 pathway. We found that the level of suppressor of cytokine signaling 3 (SOCS-3), an inhibitor of leptin signaling, is specifically increased in the ARC of DIO mice. The study suggests that the ARC is selectively leptin resistant in DIO mice and that this may be caused by elevated suppressor of cytokine signaling 3 in this hypothalamic nucleus. Defects in leptin action in the ARC may play a role in the pathogenesis of leptin-resistant obesity.
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In the citing paper
“the ability of leptin to activate pSTAT3, a marker of leptin signaling (49), is impaired in rodent models of DIO, specifically in the hypothalamic ARC (56, 124).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [124]
In the citing paper
“Importantly, P-STAT3 was not detected in the ventromedial (VMH), the dorsomedial (DMH), and the premammillary (PMV) nuclei of HA-ObRb/Pomc-Cre/Leprdb/db mice, regions known to express P-STAT3 in leptin-treated wild type mice (Figure 2C)(Munzberg et al., 2004).”
From Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons (2009) · cites this paper as Munzberg et al., 2004
In the citing paper
“Indeed, using a high-fat induced model of obesity in mice, leptin resistance measured by STAT-3 activation was shown to be restricted to the arcuate nucleus of the hypothalamus (60, 194), and this correlated with expression of the suppressor of leptin signaling SOCS-3 (248).”
From Cardiac remodeling in obesity (2008) · cites this paper as [248]
In the citing paper
“Despite this, they do not show the expected reduction in food intake and increase in energy expenditure, thus leading to the concept of leptin resistance, probably due to a decrease in JAK2‐STAT3 signaling in pathologic conditions 127.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [127]
Citations
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Morton, G. J., Cummings, D. E., Baskin, D. G., Barsh, G. S., & Schwartz, M. W. (2006) · Nature · doi:10.1038/nature05026 · Cited by 2,503
The cellular and signaling networks linking the immune system and metabolism in disease
Osborn, O., & Olefsky, J. M. (2012) · Nature Medicine · doi:10.1038/nm.2627 · Cited by 1,551
Obesity and the role of adipose tissue in inflammation and metabolism
Greenberg, A. S., & Obin, M. S. (2006) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/83.2.461s · Cited by 1,295
Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC Neurons
Vong, L., Ye, C., Yang, Z., Choi, B. J., Chua, S. C., & Lowell, B. B. (2011) · Neuron · doi:10.1016/j.neuron.2011.05.028 · Cited by 1,237
Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders
Choe, S. S., Huh, J. Y., Hwang, I. J., Kim, J. I., & Kim, J. B. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00030 · Cited by 1,206
Metadata
- Authors
- Münzberg, H., Flier, J. S., & Bjørbæk, C.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Bjørbæk, Christian
- ORCID
- Flier, Jeffrey S.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2004-11-01
- Volume
- 145
- Issue
- 11
- Pages
- 4880-4889
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2045522606
- Cited by
- 737
- References
- 61
- Citations by year
- 2026: 7 · 2025: 20 · 2024: 16 · 2023: 14 · 2022: 23 · 2021: 22 · 2020: 30 · 2019: 46 · 2018: 30 · 2017: 28 · 2016: 34 · 2015: 45 · 2014: 49 · 2013: 56 · 2012: 51
- FWCI
- 13.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK060673, R01 DK60673, R37DK028082, R37 DK 28082)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- leptin resistance, diet-induced obesity, hypothalamus, arcuate nucleus, STAT3 signaling, SOCS3, leptin receptor, high-fat diet, obesity pathogenesis
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Animals, Arcuate Nucleus of Hypothalamus, Body Weight, Dietary Fats, Dorsomedial Hypothalamic Nucleus, Eating, Hyperphagia, Male, Mice, Inbred C57BL, Obesity, Repressor Proteins, RNA, Messenger, Transcription Factors, Ventromedial Hypothalamic Nucleus, Signal Transduction, Leptin, Suppressor of Cytokine Signaling Proteins, Mice
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