Brown adipocyte ATF4 activation improves thermoregulation and systemic metabolism

Paulo, Esther; Zhang, Yun; Masand, Ruchi; Huynh, Tony; Seo, Youngho; Swaney, Danielle L.; Soucheray, Margaret; Stevenson, Erica; Jimenez-Morales, David; Krogan, Nevan J.; Wang, Biao

doi:10.1016/j.celrep.2021.109742

Cited by 18 publications

(15 citation statements)

References 97 publications

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“…Additionally, deletion of upstream ATF4 or the effector FGF21 in CoQ-deficient BAT abolished the compensatory UCP1-independent thermogenesis and metabolic modifications confirming the physiological role of an ATF4-FGF21 axis on CoQ deficient disease model in BAT. In agreement with our study illustrating the essential roles of ISR in metabolic adaptation, recent reports also showed the ATF4 is required for metabolic adaptation in the BAT-specific OPA1 and BAT-specific Lrpprc knockout animals 52,53 , We cannot exclude other metabolic modulators, such as GDF15 or small extracellular vesicles 54 , secreted from CoQ-deficient BAT activate inter-organ mitohormesis and contribute to the systemic metabolic alteration.…”

Section: Discussionsupporting

confidence: 91%

Coenzyme Q regulates UCP1 expression and thermogenesis through the integrated stress responses

Chang

Gunawan

Zushin

et al. 2022

Preprint

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Coenzyme Q (CoQ) is an essential component of mitochondrial respiration1 and required for thermogenic activity in brown adipose tissues (BAT). CoQ deficiency leads to a wide range of pathological manifestations but mechanistic consequences of CoQ deficiency in specific tissues such as BAT remain poorly understood. Here we show that pharmacological or genetic CoQ deficiency (50-75% reduction) in BAT leads to accumulation of cytosolic mitochondrial RNAs (mtRNAs) and activation of the eIF2α kinase PKR resulting in the induction of the integrated stress response (ISR) and suppression of UCP1 expression in an ATF4-dependent fashion. Surprisingly, despite diminished UCP1 levels, BAT CoQ deficiency increases whole-body metabolic rates at room temperature and thermoneutrality resulting in decreased weight gain on high fat diets (HFD). This mitohormesis like effect of BAT CoQ insufficiency is dependent on the ATF4-FGF21 axis in BAT revealing an unexpected role for CoQ in the modulation of whole-body energy expenditure with wide-ranging implications for primary and secondary CoQ deficiencies.

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Section: Discussionsupporting

confidence: 91%

Coenzyme Q regulates UCP1 expression and thermogenesis through the integrated stress responses

Chang

Gunawan

Zushin

et al. 2022

Preprint

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“…And, there are certainly physiologic situations where UCP1 expression varies as evidenced by differences in expression in humans dependent on fat mass, 37 , 38 , 39 , 40 differences in genetic strains of rodents, 41 differences related to temperature and adrenergic input, 42 , 43 or perturbation of diet. 44 …”

Section: Discussionmentioning

confidence: 99%

Membrane potential‐dependent regulation of mitochondrial complex II by oxaloacetate in interscapular brown adipose tissue

et al. 2021

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Classically, mitochondrial respiration responds to decreased membrane potential (ΔΨ) by increasing respiration. However, we found that for succinate‐energized complex II respiration in skeletal muscle mitochondria (unencumbered by rotenone), low ΔΨ impairs respiration by a mechanism culminating in oxaloacetate (OAA) inhibition of succinate dehydrogenase (SDH). Here, we investigated whether this phenomenon extends to far different mitochondria of a tissue wherein ΔΨ is intrinsically low, i.e., interscapular brown adipose tissue (IBAT). Also, to advance our knowledge of the mechanism, we performed isotopomer studies of metabolite flux not done in our previous muscle studies. In additional novel work, we addressed possible ways ADP might affect the mechanism in IBAT mitochondria. UCP1 activity, and consequently ΔΨ, were perturbed both by GDP, a well‐recognized potent inhibitor of UCP1 and by the chemical uncoupler carbonyl cyanide m‐chlorophenyl hydrazone (FCCP). In succinate‐energized mitochondria, GDP increased ΔΨ but also increased rather than decreased (as classically predicted under low ΔΨ) O2 flux. In GDP‐treated mitochondria, FCCP reduced potential but also decreased respiration. Metabolite studies by NMR and flux analyses by LC‐MS support a mechanism, wherein ΔΨ effects on the production of reactive oxygen alters the NADH/NAD+ ratio affecting OAA accumulation and, hence, OAA inhibition of SDH. We also found that ADP‐altered complex II respiration in complex fashion probably involving decreased ΔΨ due to ATP synthesis, a GDP‐like nucleotide inhibition of UCP1, and allosteric enzyme action. In summary, complex II respiration in IBAT mitochondria is regulated by UCP1‐dependent ΔΨ altering substrate flow through OAA and OAA inhibition of SDH.

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“…Here, we show that phosphorylation of the downstream mTORC1 target ribosomal protein 6 (S6) is reduced in ATF4-deficient BAT after 3 days of cold exposure, suggesting that ATF4 induction in response to cold may regulate mTORC1 pathway to promote thermogenesis in BAT. Indeed, a recent study showed that ATF4 overexpression in BAT improves cold-induced thermogenesis, which seems to be dependent on increased S6 phosphorylation, and is attenuated upon treatment with the mTOR inhibitor rapamycin (8).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, our recently published study demonstrated that deletion of the mitochondrial protein optic atrophy 1 (OPA1) in BAT lead to upregulation of Atf4 , which was required for the induction and secretion of FGF21 as a batokine and was associated with improved thermoregulation (9). Moreover, a recent study showed that selective induction of ATF4 in brown adipocytes improves cold tolerance in mice (8). Here, we tested the requirement of ATF4 and FGF21 expression in thermogenic adipocytes for cold-induced thermogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study demonstrated that the activating transcription factor 4 (ATF4), the main effector of the integrated stress response (ISR), is induced in brown adipocytes in response to cold exposure, which correlates with a significant increase in fibroblast growth factor 21 (FGF21) circulating levels (7). Furthermore, ATF4 overexpression in BAT is sufficient to improve thermogenesis in mice (8). Similarly, our recent work showed that selective deletion of the mitochondrial fusion protein optic atrophy 1 (OPA1) in BAT induces the expression and secretion of fibroblast growth factor 21 (FGF21) as a batokine, via an ATF4-dependent mechanism in mice.…”

Section: Introductionmentioning

confidence: 99%

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ATF4 Expression in Thermogenic Adipocytes is Required for Cold-Induced Thermogenesis in Mice via FGF21-Independent Mechanisms

Björkman

Marti

Jena

et al. 2023

Preprint

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In brown adipose tissue (BAT), short-term cold exposure induces the integrated stress response (ISR) main effector, activating transcription factor 4 (ATF4), and its downstream target fibroblast growth factor 21 (FGF21). We recently demonstrated that induction of ATF4 in BAT in response to mitochondrial stress is required for thermoregulation, at least in part, via induction of FGF21. In the present study, we tested the hypothesis that Atf4 and Fgf21 induction in BAT are both required for BAT thermogenesis by generating mice selectively lacking either Atf4 (ATF4 BKO) or Fgf21 (FGF21 BKO) in UCP1-expressing adipocytes. After 3 days of cold exposure, core body temperature was significantly reduced in ad-libitum-fed ATF4 BKO mice, which correlated with Fgf21 downregulation in brown and beige adipocytes, and impaired browning of white adipose tissue (WAT). Conversely, although Fgf21 deletion in thermogenic adipocytes also reduced cold-induced browning of WAT, ad libitum-fed FGF21 BKO mice had preserved core body temperature after cold exposure. When cold-exposed under fasting conditions, both ATF4 BKO and FGF21 BKO mice had reduced cold tolerance. Mechanistically, ATF4 downregulation in thermogenic adipocytes decreased amino acid import and metabolism in BAT, likely contributing to impaired brown adipocyte thermogenic capacity under ad libitum-fed conditions. Thus, Atf4 regulates Fgf21 expression in thermogenic adipocytes during cold stress, which is required to mediate cold-induced browning of iWAT but is dispensable for thermoregulation in the fed state. In contrast, in the fasted state, both Atf4 and Fgf21 expression in thermogenic adipocytes are required for thermoregulation in mice.

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Brown adipocyte ATF4 activation improves thermoregulation and systemic metabolism

Cited by 18 publications

References 97 publications

Coenzyme Q regulates UCP1 expression and thermogenesis through the integrated stress responses

Coenzyme Q regulates UCP1 expression and thermogenesis through the integrated stress responses

Membrane potential‐dependent regulation of mitochondrial complex II by oxaloacetate in interscapular brown adipose tissue

ATF4 Expression in Thermogenic Adipocytes is Required for Cold-Induced Thermogenesis in Mice via FGF21-Independent Mechanisms

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