Peripheral clock system circadian abnormalities in Cushing’s disease

Soares, V.R.X; Martins, Clarissa Silva; Martinez, Edson Zangiacomi; Araújo, Leonardo Domingues de; Roa, Silvia Liliana Ruiz; Silva, Lucas Ravagnani; Moreira, Ayrton Custódio; Castro, Margaret de

doi:10.1080/07420528.2020.1758126

Cited by 11 publications

(8 citation statements)

References 39 publications

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“…In humans, shift work at young adult age has been found to be associated with elevated cortisol levels, which were further correlated with increased body mass index 197 . Interestingly, in patients with Cushing's disease, caused by hypercortisolism and commonly accompanied by weight gain and metabolic syndrome, rhythmic clock gene expression is impaired 198 . These findings highlight the interplay between the circadian, glucocorticoid and metabolic system.…”

Section: Modern Life Challenges To the Human Circadian Systemmentioning

confidence: 98%

Mammalian circadian systems: Organization and modern life challenges

Finger

Kramer

2020

Acta Physiologica

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Humans and other mammalian species possess an endogenous circadian clock system that has evolved in adaptation to periodically reoccurring environmental changes and drives rhythmic biological functions, as well as behavioural outputs with an approximately 24‐hour period. In mammals, body clocks are hierarchically organized, encompassing a so‐called pacemaker clock in the hypothalamic suprachiasmatic nucleus (SCN), non‐SCN brain and peripheral clocks, as well as cell‐autonomous oscillators within virtually every cell type. A functional clock machinery on the molecular level, alignment among body clocks, as well as synchronization between endogenous circadian and exogenous environmental cycles has been shown to be crucial for our health and well‐being. Yet, modern life constantly poses widespread challenges to our internal clocks, for example artificial lighting, shift work and trans‐meridian travel, potentially leading to circadian disruption or misalignment and the emergence of associated diseases. For instance many of us experience a mismatch between sleep timing on work and free days (social jetlag) in our everyday lives without being aware of health consequences that may arise from such chronic circadian misalignment, Hence, this review provides an overview of the organization and molecular built‐up of the mammalian circadian system, its interactions with the outside world, as well as pathologies arising from circadian disruption and misalignment.

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Section: Modern Life Challenges To the Human Circadian Systemmentioning

confidence: 98%

Mammalian circadian systems: Organization and modern life challenges

Finger

Kramer

2020

Acta Physiologica

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“…These 2 latter studies on animal models, lacking the physiological cell circadian rhythm and an intact HPA axis, clearly demonstrated that GCs might induce or modulate the cell circadian rhythm expression and function and induce cell synchronization even in the absence of the main central or peripheral organs deputed to the generation and regulation of physiological clock system. Interestingly, the abolishment of the circadian clock machinery in the pathological human model of CD, characterized by HPA axis disruption with loss of cortisol circadian rhythm, confirms the role of endogenous GC in influencing the circadian clock in humans [14].…”

Section: Discussionmentioning

confidence: 59%

“…The interplay between HPA axis and circadian clock has been demonstrated by evidence derived from in vitro and in vivo studies on animal and/or human models [9][10][11][12][13][14][15][16][17][18][19][20][21].…”

Section: Discussionmentioning

confidence: 99%

“…Clock mutant mice displayed loss of corticosterone circadian release, drawing a flat daily curve with corticosterone constantly persisting at low levels during the entire day [12], while Per2/Cry1 double mutant mice displayed loss of ACTH and corticosterone circadian release, drawing a flat daily curve, together with a blunting of corticosterone to ACTH challenge [13]. Interestingly, in Cushing’s disease (CD), a form of CS due to a corticotroph pituitary tumor, representing a pathological human model, characterized by cortisol excess and HPA axis disruption with loss of cortisol circadian rhythm, the circadian expression of the clock genes BMAL1 , CLOCK , PER1 , PER2 , PER3 and CRY1 was abolished, differently from that found in the healthy condition, in which all the clock genes analyzed showed a physiological circadian trend [14].…”

Section: Discussionmentioning

confidence: 99%

“…An intricate interplay between the circadian clock and the hypothalamus-pituitary-adrenal (HPA) axis has been demonstrated in several in vitro and in vivo studies on animal and human models [9][10][11][12][13][14][15][16][17][18][19][20][21]. In particular, previous evidence has demonstrated that the circadian clock may control the physiological circadian endogenous glucocorticoid (GC) secretion, in in vivo animal [9][10][11][12][13] and human [14] models, and the daily physiological response to the endogenous GCs, through the activation of different mechanisms inhibiting GC receptor function, in in vitro animal [15] and human [16,17] models. On the other hand, GCs have been found to synchronize the expression of the circadian clock in in vitro animal [18] and human [19] models and in in vivo animal models [20,21].…”

Section: Introductionmentioning

confidence: 99%

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Cortisol Circadian Rhythm and Insulin Resistance in Muscle: Effect of Dosing and Timing of Hydrocortisone Exposure on Insulin Sensitivity in Synchronized Muscle Cells

et al. 2020

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Introduction/Aim: Circadian rhythm disruption is emerging as a risk factor for metabolic disorders and particularly, alterations in clock genes circadian expression have been shown to influence insulin sensitivity. Recently, the reciprocal interplay between the circadian clock machinery and HPA axis has been largely demonstrated: the circadian clock may control the physiological circadian endogenous glucocorticoids secretion and action; glucocorticoids, in turn, are potent regulator of the circadian clock and their inappropriate replacement has been associated with metabolic impairment. The aim of the current study was to investigate in vitro the interaction between the timing-of-the-day exposure to different hydrocortisone (HC) concentrations on muscle insulin sensitivity. Methods: Serum-shock synchronized mouse skeletal muscle C2C12 cells were exposed to different HC concentrations recapitulating the circulating daily physiological cortisol profile (standard cortisol profile), the circulating daily cortisol profile that reached in adrenal insufficient (AI) patients treated with once-daily MR-HC (flat cortisol profile) and treated with thrice-daily of conventional IR-HC (steep cortisol profile). The 24 hrs spontaneous oscillation of the clock genes in synchronized C2C12 cells was used to align the timing for in vitro HC exposure (Bmal1 acrophase, midphase and bathyphase) with the reference times of cortisol peaks in AI treated with IR-HC (8 am, 1 pm, 6 pm). A panel of 84 insulin sensitivity related genes and intracellular insulin signaling proteins were analyzed by RT-qPCR and western blot, respectively. Results: Only the steep profile, characterized by a higher HC exposure during Bmal1 bathyphase, produced significant downregulation in 21 insulin sensitivity-related genes. Among these, Insr, Irs1, Irs2, Pi3kca and Adipor2 were downregulated when compared the flat to the standard or steep profile. Reduced intracellular IRS1 Tyr608, AKT Ser473, AMPK Thr172 and ACC Ser79 phosphorylations were also observed. Conclusions: The current study demonstrated that is late-in-the-day cortisol exposure that modulates insulin sensitivity-related genes expression and intracellular insulin signaling in skeletal muscle cells.

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Loss of CRY2 promotes regenerative myogenesis by enhancing PAX7 expression and satellite cell proliferation

Hao

Xue

Liu

et al. 2023

MedComm

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The regenerative capacity of skeletal muscle is dependent on satellite cells. The circadian clock regulates the maintenance and function of satellite cells. Cryptochrome 2 (CRY2) is a critical component of the circadian clock, and its role in skeletal muscle regeneration remains controversial. Using the skeletal muscle lineage and satellite cell‐specific CRY2 knockout mice (CRY2 scko ), we show that the deletion of CRY2 enhances muscle regeneration. Single myofiber analysis revealed that deletion of CRY2 stimulates the proliferation of myoblasts. The differentiation potential of myoblasts was enhanced by the loss of CRY2 evidenced by increased expression of myosin heavy chain (MyHC) and myotube formation in CRY2 −/− cells versus CRY2 +/+ cells. Immunostaining revealed that the number of mononucleated paired box protein 7 (PAX7 + ) cells associated with myotubes formed by CRY2 −/− cells was increased compared with CRY2 +/+ cells, suggesting that more reserve cells were produced in the absence of CRY2. Loss of CRY2 leads to the activation of the ERK1/2 signaling pathway and ETS1, which binds to the promoter of PAX7 to induce its transcription. CRY2 deficient myoblasts survived better in ischemic muscle. Therefore, CRY2 is essential in regulating skeletal muscle repair.

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Peripheral clock system circadian abnormalities in Cushing’s disease

Cited by 11 publications

References 39 publications

Mammalian circadian systems: Organization and modern life challenges

Mammalian circadian systems: Organization and modern life challenges

Cortisol Circadian Rhythm and Insulin Resistance in Muscle: Effect of Dosing and Timing of Hydrocortisone Exposure on Insulin Sensitivity in Synchronized Muscle Cells

Loss of CRY2 promotes regenerative myogenesis by enhancing PAX7 expression and satellite cell proliferation

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