STK3/STK4 signalling in adipocytes regulates mitophagy and energy expenditure

Cho, Yoon Keun; Son, Yeonho; Saha, Abhirup; Kim, Doeun; Choi, Cheoljun; Kim, Minsu; Park, Ji Hyun; Im, Hyeonyeong; Han, Jeong‐Won; Kim, Kyungmin; Jung, Young Suk; Yun, Jeanho; Bae, Eun Ju; Seong, Je Kyung; Lee, Mi Ock; Lee, Sangkyu; Granneman, James G.; Lee, Yun Hee

doi:10.1038/s42255-021-00362-2

Cited by 34 publications

(33 citation statements)

References 62 publications

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“…STK3 and STK4 are highly expressed in ''white-appearing'' (unstimulated) adipocytes and downregulated during cold exposure. Genetic loss or inhibition of STK3/4 activity increases mitochondrial content and uncoupled respiratory activity in beige and brown adipocytes via reducing mitophagy (Cho et al, 2021). Remarkably, inhibiting mitochondrial clearance in the above mouse models ameliorates obesity and improves systemic metabolism, though this may be expected to cause aberrant mitochondrial function over the long-term.…”

Section: Adipose-tissue Whiteningmentioning

confidence: 99%

Adipose-tissue plasticity in health and disease

Sakers

Siqueira

Seale

et al. 2022

Cell

366

216

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Section: Adipose-tissue Whiteningmentioning

confidence: 99%

Adipose-tissue plasticity in health and disease

Sakers

Siqueira

Seale

et al. 2022

Cell

366

216

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“…Next, cells were cultured in adipogenic differentiation media (growth media containing 0.125 mmol/L indomethacin [70270; Cayman Chemical, Ann Arbor, MI], 2.5 mmol/L isobutyl methylxanthine [I5879; Cayman Chemical], 1 mmol/L dexamethasone [D4902; Cayman Chemical], 10 mg/mL insulin [I9278; Sigma-Aldrich], and 1 nmol/L triiodothyronine [16028; Cayman]) for 3 days. Then the cells were maintained in growth media containing 10 mg/mL insulin and 1 nmol/L triiodothyronine for 3 days (28). For the chemical inhibition of TM4SF5, 5 mmol/L of 4 0 -(p-toluenesulfonylamido)-4-hydroxychalcone (TSAHC) (19) was treated for 24 h.…”

Section: Cell Culturementioning

confidence: 99%

“…Oxygen consumption rate (OCR) was measured with Seahorse XF Analyzers as previously described (28). The coupling efficiency was determined with the following equation: 1 À uncoupled respiration/basal OCR (30,31).…”

Section: Cell Culturementioning

confidence: 99%

TM4SF5 Knockout Protects Mice From Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue

et al. 2021

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Transmembrane 4 L six family member 5 (TM4SF5) functions as a sensor for lysosomal arginine levels and activates the mammalian target of rapamycin complex 1 (mTORC1). While the mTORC1 signaling pathway plays a key role in adipose tissue metabolism, the regulatory function of TM4SF5 in adipocytes remains unclear. In this study we aimed to establish a TM4SF5 knockout (KO) mouse model and investigated the effects of TM4SF5 KO on mTORC1 signaling–mediated autophagy and mitochondrial metabolism in adipose tissue. TM4SF5 expression was higher in inguinal white adipose tissue (iWAT) than in brown adipose tissue and significantly upregulated by a high-fat diet (HFD). TM4SF5 KO reduced mTORC1 activation and enhanced autophagy and lipolysis in adipocytes. RNA sequencing analysis of TM4SF5 KO mouse iWAT showed that the expression of genes involved in peroxisome proliferator–activated receptor α signaling pathways and mitochondrial oxidative metabolism was upregulated. Consequently, TM4SF5 KO reduced adiposity and increased energy expenditure and mitochondrial oxidative metabolism. TM4SF5 KO prevented HFD-induced glucose intolerance and inflammation in adipose tissue. Collectively, the results of our study demonstrate that TM4SF5 regulates autophagy and lipid catabolism in adipose tissue and suggest that TM4SF5 could be therapeutically targeted for the treatment of obesity-related metabolic diseases.

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“…Here, we have focussed on two of these processes, mitosis (Figure 1) and cellular migration (Figure 2). Many more examples are described elsewhere, such as integration of processes and organelles at the plasma membrane [12], cell size [132], mechanotransduction [31], fibrosis [46,47], cell polarity [146][147][148], metabolism [40,132,[134][135][136]149], integration with auto- [150] and mito-phagy [151], in great part through interaction with numerous other cellular pathways [7]. These multilevel feedback loops are likely in place to dampen noise and prevent signal fluctuations, and to further integrate inputs from the cellular microenvironment [31,[152][153][154].…”

Section: Discussionmentioning

confidence: 99%

Cellular feedback dynamics and multilevel regulation driven by the hippo pathway

Park

2021

Biochemical Society Transactions

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The Hippo pathway is a dynamic cellular signalling nexus that regulates differentiation and controls cell proliferation and death. If the Hippo pathway is not precisely regulated, the functionality of the upstream kinase module is impaired, which increases nuclear localisation and activity of the central effectors, the transcriptional co-regulators YAP and TAZ. Pathological YAP and TAZ hyperactivity consequently cause cancer, fibrosis and developmental defects. The Hippo pathway controls an array of fundamental cellular processes, including adhesion, migration, mitosis, polarity and secretion of a range of biologically active components. Recent studies highlight that spatio-temporal regulation of Hippo pathway components are central to precisely controlling its context-dependent dynamic activity. Several levels of feedback are integrated into the Hippo pathway, which is further synergized with interactors outside of the pathway that directly regulate specific Hippo pathway components. Likewise, Hippo core kinases also ‘moonlight’ by phosphorylating multiple substrates beyond the Hippo pathway and thereby integrates further flexibility and robustness in the cellular decision-making process. This topic is still in its infancy but promises to reveal new fundamental insights into the cellular regulation of this therapeutically important pathway. We here highlight recent advances emphasising feedback dynamics and multilevel regulation of the Hippo pathway with a focus on mitosis and cell migration, as well as discuss potential productive future research avenues that might reveal novel insights into the overall dynamics of the pathway.

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STK3/STK4 signalling in adipocytes regulates mitophagy and energy expenditure

Cited by 34 publications

References 62 publications

Adipose-tissue plasticity in health and disease

Adipose-tissue plasticity in health and disease

TM4SF5 Knockout Protects Mice From Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue

Cellular feedback dynamics and multilevel regulation driven by the hippo pathway

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