The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis

Mouchiroud, Mathilde; Camiré, Étienne; Aldow, Manal; Caron, Alexandre; Jubinville, Éric; Turcotte, Laurie; Kaci, Inès; Beaulieu, Marianne; Roy, Christian; Labbé, Sébastien M.; Varin, Thibault; Gélinas, Yves; Lamothe, Jennifer; Trottier, Jocelyn; Mitchell, Patricia L.; Guénard, Frédéric; Festuccia, William T.; Joubert, Philippe; Rose, Christopher F.; Karvellas, Constantine J.; Barbier, Olivier; Morissette, Mathieu C.; Marette, André; Laplante, Mathieu

doi:10.1172/jci.insight.129492

Cited by 44 publications

(67 citation statements)

References 77 publications

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“…Tsukushi (TSK) is an atypical member of the small leucine-rich proteoglycan family that controls developmental processes in various organisms [6]. Recently, two groups, including ours, reported the identification of TSK as a new hepatokine [[7], [8], [9]]. These studies revealed that TSK is a liver-derived factor whose expression and circulating levels are strongly induced in response to obesity and cold exposure.…”

Section: Introductionmentioning

confidence: 99%

The Hepatokine TSK does not affect brown fat thermogenic capacity, body weight gain, and glucose homeostasis

Mouchiroud

Camiré

Aldow

et al. 2019

Molecular Metabolism

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ObjectivesHepatokines are proteins secreted by the liver that impact the functions of the liver and various tissues through autocrine, paracrine, and endocrine signaling. Recently, Tsukushi (TSK) was identified as a new hepatokine that is induced by obesity and cold exposure. It was proposed that TSK controls sympathetic innervation and thermogenesis in brown adipose tissue (BAT) and that loss of TSK protects against diet-induced obesity and improves glucose homeostasis. Here we report the impact of deleting and/or overexpressing TSK on BAT thermogenic capacity, body weight regulation, and glucose homeostasis.MethodsWe measured the expression of thermogenic genes and markers of BAT innervation and activation in TSK-null and TSK-overexpressing mice. Body weight, body temperature, and parameters of glucose homeostasis were also assessed in the context of TSK loss and overexpression.ResultsThe loss of TSK did not affect the thermogenic activation of BAT. We found that TSK-null mice were not protected against the development of obesity and did not show improvement in glucose tolerance. The overexpression of TSK also failed to modulate thermogenesis, body weight gain, and glucose homeostasis in mice.ConclusionsTSK is not a significant regulator of BAT thermogenesis and is unlikely to represent an effective target to prevent obesity and improve glucose homeostasis.

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Section: Introductionmentioning

confidence: 99%

The Hepatokine TSK does not affect brown fat thermogenic capacity, body weight gain, and glucose homeostasis

Mouchiroud

Camiré

Aldow

et al. 2019

Molecular Metabolism

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“…Previous studies suggest that TSK acts as a hormonal checkpoint that suppresses adipose tissue sympathetic innervation, adrenergic action and thermogenesis, and attenuates energy expenditure (20). In animal models, TSK deficiency protected mice from high-fat diet induced obesity (20,22). In contrast, Mouchiroud et al reported that TSK did not affect brown fat thermogenic capacity or body weight gain in TSK knockout mice model (30).…”

Section: Discussionmentioning

confidence: 98%

“…Recent studies have shown that altered thyroid status can affect circulating levels of several cytokines secreted from the liver, which may be involved in the thyroid hormone signaling network to modulate whole-body glucose and lipid homeostasis ( 13 , 15 , 28 , 29 ). Wang et al identified TSK as a liver-enriched secreted factor that was remarkably induced by T3 treatment or cold exposure in animal models, and was tightly linked to the activation of thermogenesis and energy expenditure ( 20 – 22 ). Unfortunately, information regarding the association of circulating TSK with thyroid function and energy expenditure in humans was limited.…”

Section: Discussionmentioning

confidence: 99%

“…Thyroid hormone regulates cholesterol and bile acid homeostasis through direct induction of sterol response element binding protein 2 (SREBP-2) and CPY7A1 gene expression as well as cross-talk with other nuclear receptors, such as peroxisome proliferator-activated receptor α (PPARα) and liver X receptor α pathway ( 8 , 9 , 32 – 34 ). Similarly, studies indicated that TSK affect cholesterol homeostasis by modulating circulating HDL-cholesterol, reversing cholesterol transport, and bile acids synthesis in the liver ( 22 ). Furthermore, previous study also reported that TSK deficiency can significantly improve insulin sensitivity and glucose tolerance in animal model ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

“…Wang et al have identified TSK as a hepatokine that is tightly linked to the activation of thermogenesis and energy expenditure ( 20 ). Previous studies have shown that TSK impacts systemic cholesterol homeostasis by lowering circulating high-density lipoprotein cholesterol and cholesterol efflux capacity, and acts as a blood biomarker of liver stress linking non-alcoholic steatohepatitis (NASH) and the development of atherogenic dyslipidemia and atherosclerosis ( 21 , 22 ). Evidence indicated that hepatic TSK expression and secretion were strongly induced by stimuli which increased thermogenesis and energy expenditure, such as thyroid hormone, adrenergic agonist and cold exposure and TSK was identified as a negative regulator of sympathetic innervation in brown fat, and suppressed thyroid hormone expression and catecholamine synthesis ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

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Elevated Serum Tsukushi Levels in Patients With Hyperthyroidism

et al. 2020

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Background: Tsukushi (TSK) is a secreted hepatokine recently identified as playing an important role in modulating glucose and lipid metabolism, and systemic energy homeostasis. However, information is not available regarding the association between circulating TSK and hyperthyroidism in humans. Methods: We measured serum TSK levels in 180 patients with hyperthyroidism and 82 healthy controls recruited from the clinic. Of them, 46 hyperthyroid patients received thionamide treatment for 3 months. Results: Hyperthyroid patients had higher levels of circulating TSK than healthy controls [186.67 (133.63-280.59) ng/ml vs. 97.27 (77.87-146.96) ng/ml, P < 0.001]. Subjects with higher level of serum free triiodothyronine (T3) and free thyroxine (T4) had higher levels of circulating TSK. In addition, serum TSK levels markedly declined with the improvement of thyroid function after thionamide treatment. In multivariable linear regression analyses, circulating TSK concentrations were significantly associated with serum free T3, free T4, thyroid stimulating hormone, thyrotropin receptor antibody, total cholesterol, low-density lipoprotein cholesterol (LDL-cholesterol), high-density lipoprotein cholesterol (HDL-cholesterol), and basal metabolic rate (all P < 0.01), adjusting for age, gender, smoking, and body mass index (BMI). Importantly, circulating TSK was significantly associated with risks of hyperthyroidism in multivariable logistic regression analyses, adjusting for age, gender, smoking, BMI, fasting glucose, LDL-cholesterol, and insulin resistance (HOMA-IR) [OR (95% CI), 1.012(1.005-1.019), P = 0.001]. Conclusion: These findings indicate that circulating TSK concentrations are independently associated with hyperthyroidism, suggesting that circulating TSK may be a predictive factor of hyperthyroidism and can be used for therapeutic monitoring.

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Hepatokine Pregnancy Zone Protein Governs the Diet‐Induced Thermogenesis Through Activating Brown Adipose Tissue

et al. 2021

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Intermittent fasting (IF), as a dietary intervention for weight loss, takes effects primarily through increasing energy expenditure. However, whether inter‐organ systems play a key role in IF remains unclear. Here, a novel hepatokine, pregnancy zone protein (PZP) is identified, which has significant induction during the refeeding stage of IF. Further, loss of function studies and protein therapeutic experiment in mice revealed that PZP promotes diet‐induced thermogenesis through activating brown adipose tissue (BAT). Mechanistically, circulating PZP can bind to cell surface glucose‐regulated protein of 78 kDa (GRP78) to promote uncoupling protein 1 (UCP1) expression via a p38 MAPK‐ATF2 signaling pathway in BAT. These studies illuminate a systemic regulation in which the IF promotes BAT thermogenesis through the endocrinal system and provide a novel potential target for treating obesity and related disorders.

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The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis

Cited by 44 publications

References 77 publications

The Hepatokine TSK does not affect brown fat thermogenic capacity, body weight gain, and glucose homeostasis

The Hepatokine TSK does not affect brown fat thermogenic capacity, body weight gain, and glucose homeostasis

Elevated Serum Tsukushi Levels in Patients With Hyperthyroidism

Hepatokine Pregnancy Zone Protein Governs the Diet‐Induced Thermogenesis Through Activating Brown Adipose Tissue

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