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Cited by 311Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesHypothalamic control of reproductive hormones

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Hyperleptinemia Is Required for the Development of Leptin Resistance

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Knight, Zachary A., Hannan, K. Schot, Greenberg, Matthew L., Friedman, Jeffrey M.·2010·PLoS ONE
DOI 10.1371/journal.pone.0011376PMC PMC2894068
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Abstract

Leptin regulates body weight by signaling to the brain the availability of energy stored as fat. This negative feedback loop becomes disrupted in most obese individuals, resulting in a state known as leptin resistance. The physiological causes of leptin resistance remain poorly understood. Here we test the hypothesis that hyperleptinemia is required for the development of leptin resistance in diet-induced obese mice. We show that mice whose plasma leptin has been clamped to lean levels develop obesity in response to a high-fat diet, and the magnitude of this obesity is indistinguishable from wild-type controls. Yet these obese animals with constant low levels of plasma leptin remain highly sensitive to exogenous leptin even after long-term exposure to a high fat diet. This shows that dietary fats alone are insufficient to block the response to leptin. The data also suggest that hyperleptinemia itself can contribute to leptin resistance by downregulating cellular response to leptin as has been shown for other hormones.

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Figure 1 Energy balance in wild-type and ob-normalized animals on low and high-fat diets. A. Schematic of experimental strategy. Wild-type and ob/ob animals were implanted with pumps dispensing PBS or leptin, respectively, at 4 weeks of age, and pumps were replaced every four weeks as indicated by red arrows. Leptin sensitivity was assayed at 26 weeks of age. B. Body weight of wild-type (black) and ob-norm (red) mice on a high-fat or low-fat diet. C. Body fat percentage of wild-type and ob-norm mice at 14 and 18 weeks of age that were maintained on a high-fat diet (open bars) or low-fat diet (filled bars). D. Daily food intake for wild-type (black) and ob-norm (red) mice on a low-fat diet. p>0.05 for wild-type vs. ob-norm at all time points. E. Daily food intake for wild-type (black) and ob-norm (red) mice on a high-fat diet. * indicates p<0.05. F. Plasma leptin concentrations of wild-type and ob-norm mice at 18 and 26 weeks of age that were maintained on a high-fat diet (open bars) or low-fat diet (filled bars). All error bars are +/− SEM.
Figure 1 Energy balance in wild-type and ob-normalized animals on low and high-fat diets. A. Schematic of experimental strategy. Wild-type and ob/ob animals were implanted with pumps dispensing PBS or leptin, respectively, at 4 weeks of age, and pumps were replaced every four weeks as indicated by red arrows. Leptin sensitivity was assayed at 26 weeks of age. B. Body weight of wild-type (black) and ob-norm (red) mice on a high-fat or low-fat diet. C. Body fat percentage of wild-type and ob-norm mice at 14 and 18 weeks of age that were maintained on a high-fat diet (open bars) or low-fat diet (filled bars). D. Daily food intake for wild-type (black) and ob-norm (red) mice on a low-fat diet. p>0.05 for wild-type vs. ob-norm at all time points. E. Daily food intake for wild-type (black) and ob-norm (red) mice on a high-fat diet. * indicates p<0.05. F. Plasma leptin concentrations of wild-type and ob-norm mice at 18 and 26 weeks of age that were maintained on a high-fat diet (open bars) or low-fat diet (filled bars). All error bars are +/− SEM.CC BY · PubMed Central
Figure 2 Glucose metabolism and energy expenditure. A. Plasma glucose concentrations in ad libitum fed wild-type and ob-norm mice that were maintained on a high-fat diet (open bars) or low-fat diet (filled bars). B. Plasma insulin concentrations of wild-type and ob-norm mice at 18 and 26 weeks of age that were maintained on a high-fat diet (open bars) or low-fat diet (filled bars). C. Plasma glucose concentrations in response to a glucose injection in wild-type (black) and ob-norm (red) mice. Triangles represent mice on a low-fat diet and squares represent mice on a high-fat diet. * indicates p<0.05. D. Average beam breaks per minute for wild-type and ob-norm mice maintained on a low-fat (filled bar) or high-fat (open bar) diet. E. Average oxygen consumption for wild-type and ob-norm mice in the light phase (open bars) and dark phase (closed bars).
Figure 2 Glucose metabolism and energy expenditure. A. Plasma glucose concentrations in ad libitum fed wild-type and ob-norm mice that were maintained on a high-fat diet (open bars) or low-fat diet (filled bars). B. Plasma insulin concentrations of wild-type and ob-norm mice at 18 and 26 weeks of age that were maintained on a high-fat diet (open bars) or low-fat diet (filled bars). C. Plasma glucose concentrations in response to a glucose injection in wild-type (black) and ob-norm (red) mice. Triangles represent mice on a low-fat diet and squares represent mice on a high-fat diet. * indicates p<0.05. D. Average beam breaks per minute for wild-type and ob-norm mice maintained on a low-fat (filled bar) or high-fat (open bar) diet. E. Average oxygen consumption for wild-type and ob-norm mice in the light phase (open bars) and dark phase (closed bars).CC BY · PubMed Central
Figure 3 Leptin sensitivity in a 12-day infusion. A. Body weight of wild-type animals that received a leptin (red) or PBS (black) infusion for 12-days (gray block). B. Body weight of ob-norm animals that received a leptin (red) or PBS (black) infusion for 12-days (gray block). C. Difference in weight loss between leptin and vehicle for each cohort over the 12-day leptin infusion. Values are expressed as percentage change in body weight. D. Average daily food intake during the 12-day infusion for animals in each cohort.
Figure 3 Leptin sensitivity in a 12-day infusion. A. Body weight of wild-type animals that received a leptin (red) or PBS (black) infusion for 12-days (gray block). B. Body weight of ob-norm animals that received a leptin (red) or PBS (black) infusion for 12-days (gray block). C. Difference in weight loss between leptin and vehicle for each cohort over the 12-day leptin infusion. Values are expressed as percentage change in body weight. D. Average daily food intake during the 12-day infusion for animals in each cohort.CC BY · PubMed Central
Figure 4 STAT3 phosphorylation in response to acute leptin injection. A. Staining for pSTAT3 in the mediobasal hypothalamus of mice on a low-fat diet given an intraperitoneal injection of either leptin or vehicle. B. Staining for pSTAT3 in the mediobasal hypothalamus of mice on a high-fat diet given an intraperitoneal injection of either leptin or vehicle. C. Quantitation of pSTAT3 positive cells in the arcuate nucleus for mice on a low-fat diet. D. Quantitation of pSTAT3 positive cells in the arcuate nucleus for mice on a high-fat diet.
Figure 4 STAT3 phosphorylation in response to acute leptin injection. A. Staining for pSTAT3 in the mediobasal hypothalamus of mice on a low-fat diet given an intraperitoneal injection of either leptin or vehicle. B. Staining for pSTAT3 in the mediobasal hypothalamus of mice on a high-fat diet given an intraperitoneal injection of either leptin or vehicle. C. Quantitation of pSTAT3 positive cells in the arcuate nucleus for mice on a low-fat diet. D. Quantitation of pSTAT3 positive cells in the arcuate nucleus for mice on a high-fat diet.CC BY · PubMed Central

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  1. MF White, 2006, Regulating insulin signaling and beta-cell function through IRS proteins., Can J Physiol Pharmacol, 84, 725

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Metadata

Authors
Knight, Z. A., Hannan, K. S., Greenberg, M. L., & Friedman, J. M.
Affiliations
Howard Hughes Medical Institute (US)
Corresponding author
Friedman, Jeffrey M.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2010-06-29
Volume
5
Issue
6
Pages
e11376
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0011376
PMC
PMC2894068
OpenAlex
W1974838371
Cited by
311
References
53
Citations by year
2026: 12 · 2025: 17 · 2024: 17 · 2023: 16 · 2022: 21 · 2021: 21 · 2020: 31 · 2019: 21 · 2018: 20 · 2017: 22 · 2016: 19 · 2015: 23 · 2014: 19 · 2013: 14 · 2012: 15
FWCI
7.37
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health (DK083531)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK083531, R00DK083531, DK041096, K99DK083531, R01DK041096)
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
hyperleptinemia, leptin resistance, diet-induced obesity, leptin signaling, high-fat diet, leptin sensitivity, obesity, energy homeostasis
MeSH terms
Animals, Energy Intake, Feeding Behavior, Mice, Inbred C57BL, Obesity, Leptin, Mice

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