Circadian dysfunction induces leptin resistance in mice
Open accessAbstract
Circadian disruption is associated with obesity, implicating the central clock in body weight control. Our comprehensive screen of wild-type and three circadian mutant mouse models, with or without chronic jet lag, shows that distinct genetic and physiologic interventions differentially disrupt overall energy homeostasis and Leptin signaling. We found that BMAL1/CLOCK generates circadian rhythm of C/EBPα-mediated leptin transcription in adipose. Per and Cry mutant mice show similar disruption of peripheral clock and deregulation of leptin in fat, but opposite body weight and composition phenotypes that correlate with their distinct patterns of POMC neuron deregulation in the arcuate nucleus. Chronic jet lag is sufficient to disrupt the endogenous adipose clock and also induce central Leptin resistance in wild-type mice. Thus, coupling of the central and peripheral clocks controls Leptin endocrine feedback homeostasis. We propose that Leptin resistance, a hallmark of obesity in humans, plays a key role in circadian dysfunction-induced obesity and metabolic syndromes.
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Liver pathology in jet-lagged WT and mutant mice, including Cry-mutants deficient in fat storage in adipose, initiated with spontaneous NAFLD onset at a young age.
“Liver pathology in jet-lagged WT and mutant mice, including Cry-mutants that are deficient in fat storage in adipose (Kettner et al., 2015), initiated with spontaneous NAFLD onset at a young age.”
From Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis (2016) · cites this paper as Kettner et al., 2015
Chronic circadian disruption is sufficient to induce leptin resistance in mice independent of diet choice and the time or amount of food intake.
“We have reported recently that chronic circadian disruption is sufficient to induce Leptin resistance in mice independent of diet choice and the time or amount of food intake (Kettner et al., 2015).”
From Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis (2016) · cites this paper as Kettner et al., 2015
The role of circadian dysfunction in spontaneous cancer initiation in humans cannot be closely modeled by mutant mice with germline or tissue-specific ablation of circadian genes because they do not show the same circadian dynamics as normal humans in response to environmental changes.
“the role of circadian dysfunction in spontaneous cancer initiation in humans cannot be closely modeled by these mutant mice as they do not display the same circadian dynamics as normal human individuals in response to changes in environmental cues (Kettner et al., 2015).”
From Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis (2016) · cites this paper as Kettner et al., 2015
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References 53 · Cited by 260
- Authors
- Kettner, N. M., Mayo, S. A., Hua, J., Lee, C., Moore, D. D., & Fu, L.
- Affiliations
- Agricultural Research Service (US)
- Florida State University (US)
- Baylor College of Medicine (US)
- Corresponding author
- Moore, David D.
- Fu, Loning
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 22
- Issue
- 3
- Pages
- 448-459
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4558341
- OpenAlex
- W1506494112
- Cited by
- 260
- References
- 53
- Citations by year
- 2026: 10 · 2025: 21 · 2024: 27 · 2023: 24 · 2022: 34 · 2021: 35 · 2020: 29 · 2019: 15 · 2018: 24 · 2017: 24 · 2016: 14 · 2015: 3
- FWCI
- 12.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1s10od016167-01)
- National Cancer Institute (R01CA137019, R01 CA137019-01A)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK56338, T32DK007696, P30DK056338)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083092)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- circadian dysfunction, leptin resistance, obesity, jet lag, C/EBPα, POMC neurons, arcuate nucleus, energy homeostasis, metabolic syndrome
- MeSH terms
- Adipose Tissue, Animals, Base Sequence, Body Weight, Circadian Rhythm, Energy Metabolism, Mice, Inbred C57BL, Obesity, Signal Transduction, Transcriptional Activation, Leptin, Mice, Melanocortins, CLOCK Proteins, Circadian Clocks
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