Region-Specific Leptin Resistance within the Hypothalamus of Diet-Induced Obese Mice

Münzberg, Heike; Flier, Jeffrey S.; Bjørbæk, Christian

doi:10.1210/en.2004-0726

Cited by 737Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesHypothalamic control of reproductive hormones

Region-Specific Leptin Resistance within the Hypothalamus of Diet-Induced Obese Mice

Münzberg, Heike, Flier, Jeffrey S., Bjørbæk, Christian·2004·Endocrinology

DOI 10.1210/en.2004-0726

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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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The ability of leptin to activate pSTAT3 is impaired in rodent models of diet-induced obesity, specifically in the hypothalamic arcuate nucleus.
“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]
P-STAT3 was not detected in the VMH, DMH, and PMV nuclei of HA-ObRb/Pomc-Cre/Leprdb/db mice.
“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 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, and this correlated with expression of the suppressor of leptin signaling SOCS-3.
“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]
Obese humans and DIO mice do not show the expected reduction in food intake and increase in energy expenditure, leading to the concept of leptin resistance, probably due to a decrease in JAK2‐STAT3 signaling in pathologic conditions.
“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]

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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
DOI: 10.1210/en.2004-0726
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 › Epidemiology › 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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Region-Specific Leptin Resistance within the Hypothalamus of Diet-Induced Obese Mice

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