Circadian Dysfunction Induces Leptin Resistance in Mice

Kettner, Nicole M.; Mayo, Sara A.; Hua, Jack; Lee, Choogon; Moore, David D.; Fu, Loning

doi:10.1016/j.cmet.2015.06.005

Cited by 202 publications

(174 citation statements)

References 55 publications

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“…A bidirectional link between the circadian system and leptin signalling has previously been described in mammals (Kettner et al 2015). In adipose tissue, the rhythmic binding of the BMAL1/CLOCK heterodimer to the leptin promoter potentiates C/EBPα-mediated leptin transcription during the early sleeping phase in mice (Mus musculus).…”

Section: Leptinmentioning

confidence: 95%

“…However, there is currently no direct evidence that the peripheral clock regulates leptin transcription in fishes, although bmal1a and clock1a transcripts are rhythmic in the goldfish liver, exhibiting acrophases during the light phase (Sánchez-Bretaño 2016) that precede the peak in leptin expression (Tinoco et al 2014). In mice, such regulation by the adipose clockwork is sufficient to drive diurnal oscillations of serum leptin, and the SCN pacemaker rhythmically potentiates the leptin-responsive neurons (Kettner et al 2015). Therefore, this may explain the time-dependent effects of leptin on food intake in goldfish (Vivas et al 2011).…”

Section: Leptinmentioning

confidence: 99%

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Interplay between the endocrine and circadian systems in fishes

Isorna

Pedro

Valenciano

et al. 2017

Journal of Endocrinology

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The circadian system is responsible for the temporal organisation of physiological functions which, in part, involves daily cycles of hormonal activity. In this review, we analyse the interplay between the circadian and endocrine systems in fishes. We first describe the current model of fish circadian system organisation and the basis of the molecular clockwork that enables different tissues to act as internal pacemakers. This system consists of a net of central and peripherally located oscillators and can be synchronised by the light-darkness and feeding-fasting cycles. We then focus on two central neuroendocrine transducers (melatonin and orexin) and three peripheral hormones (leptin, ghrelin and cortisol), which are involved in the synchronisation of the circadian system in mammals and/or energy status signalling. We review the role of each of these as overt rhythms (i.e. outputs of the circadian system) and, for the first time, as key internal temporal messengers that act as inputs for other endogenous oscillators. Based on acute changes in clock gene expression, we describe the currently accepted model of endogenous oscillator entrainment by the light-darkness cycle and propose a new model for non-photic (endocrine) entrainment, highlighting the importance of the bidirectional cross-talking between the endocrine and circadian systems in fishes. The flexibility of the fish circadian system combined with the absence of a master clock makes these vertebrates a very attractive model for studying communication among oscillators to drive functionally coordinated outputs.

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Section: Leptinmentioning

confidence: 95%

Section: Leptinmentioning

confidence: 99%

Interplay between the endocrine and circadian systems in fishes

Isorna

Pedro

Valenciano

et al. 2017

Journal of Endocrinology

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“…It is possible that overall CPT levels are similar but that its enzymatic activity in general is reduced in Per1/2 −/− mice. In this respect, leptin was shown to increase liver CPT1 activity (29), and recently, it was found to be disregulated in PER1/2 null mice (30). In addition, potential differences in the levels of malonyl CoA that inhibit CPT1 activity (25) and posttranslational modifications of CPT1 (31) may also account for differences in its overall activity levels.…”

Section: Diurnal Oscillations In Mitochondrial Respiration In Responsmentioning

confidence: 99%

Circadian control of oscillations in mitochondrial rate-limiting enzymes and nutrient utilization by PERIOD proteins

Neufeld-Cohen

Robles

Aviram

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

195

187

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Mitochondria are major suppliers of cellular energy through nutrients oxidation. Little is known about the mechanisms that enable mitochondria to cope with changes in nutrient supply and energy demand that naturally occur throughout the day. To address this question, we applied MS-based quantitative proteomics on isolated mitochondria from mice killed throughout the day and identified extensive oscillations in the mitochondrial proteome. Remarkably, the majority of cycling mitochondrial proteins peaked during the early light phase. We found that rate-limiting mitochondrial enzymes that process lipids and carbohydrates accumulate in a diurnal manner and are dependent on the clock proteins PER1/2. In this conjuncture, we uncovered daily oscillations in mitochondrial respiration that peak during different times of the day in response to different nutrients. Notably, the diurnal regulation of mitochondrial respiration was blunted in mice lacking PER1/2 or on a high-fat diet. We propose that PERIOD proteins optimize mitochondrial metabolism to daily changes in energy supply/demand and thereby, serve as a rheostat for mitochondrial nutrient utilization.M itochondria serve as major suppliers of cellular energy through nutrient oxidation. One of the major challenges that mitochondria face is the adaptation to changes in nutrient supply and energy demand. An inability of mitochondria to deal with altered nutrient environment is associated with metabolic diseases, such as diabetes and obesity (1, 2).Mitochondria oxidize carbohydrates and lipids to generate ATP by a process known as oxidative phosphorylation. Pyruvate and fatty acids are transported from the cytoplasm into the mitochondrial matrix, where they are catabolized into acetyl CoA. Pyruvate is converted to acetyl CoA through the action of the pyruvate dehydrogenase complex (PDC), whereas fatty acids are oxidized through a cycle of reactions that trim two carbons at a time, generating one molecule of acetyl CoA in each cycle [i.e., fatty acid oxidation (FAO)]. The acetyl groups are then fed into the Krebs cycle for additional degradation, and the process culminates with the transfer of acetyl-derived high-energy electrons along the respiratory chain.Mounting evidence suggests that circadian clocks orchestrate our daily physiology and metabolism (3-6). The mammalian circadian timing system consists of a central pacemaker in the brain that is entrained by daily light-dark cycles and synchronizes subsidiary oscillators in virtually all cells of the body, in part by driving rhythmic feeding behavior. The core clock molecular circuitry relies on interlocked transcription-translation feedback loops that generate daily oscillations of gene expression in cultured cells and living animals (7). Many transcriptomes (8-12) and more recently, several proteomics (13-15) and metabolomics studies (16-21) highlighted the pervasive circadian control of metabolism.Rest-activity and feeding-fasting cycles that naturally occur throughout the day impose pronounced changes in nutrient s...

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“…While Cry double-mutant mice show dampened feeding rhythms on normal chow diet (NCD) and HFD, they are generally lighter and leaner than wild-type controls. 7,40,68 Under HFD, however, they rapidly gain weight despite a lower food intake compared to wild types. 40 This effect is explained by an enhanced potential of Cry-mutant adipocytes for lipid uptake and insulin-stimulated lipogenesis, making them highly susceptible to HFD-induced obesity.…”

Section: -60mentioning

confidence: 99%

“…48,61 Mice with mutations in the gene encoding the CLOCK partner protein BMAL1 show less ambiguous phenotypes with elevated adiposity, despite unaffected food intake. 7,35,[62][63][64][65][66][67] This could be explained by the WNT-mediated suppressive effect of Bmal1 on adipogenesis. 35 However, since Bmal1 knockout (KO) mice show an early aging phenotype, the adipose phenotype can only be observed in young animals.…”

Section: -60mentioning

confidence: 99%