Critical roles of nardilysin in the maintenance of body temperature homoeostasis

Hiraoka, Yutaka; Matsuoka, Toshihiro; Ohno, Mikiko; Nakamura, Kazuhiro; Saijo, Sayaka; Matsumura, Shigenobu; Nishi, Kiyoto; Sakamoto, Jiro; Chen, Po‐Min; Inoue, Kazuo; Fushiki, Tohru; Kita, Toru; Kimura, Takeshi; Nishi, Eiichiro

doi:10.1038/ncomms4224

Cited by 36 publications

(54 citation statements)

References 47 publications

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“…Cold exposure increases PGC1α expression in BAT in mice and in subcutaneous fat in humans (150, 170). PGC1α stimulates UCP1 expression and thermogenesis in brown and beige adipocytes by acting as a coactivator for many transcription factors, including PPAR family members, C/EBP family members, Tbx15, N-arginine dibasic convertase (Nrd1/NRDc, also called nardilysin), and IRF4 (91, 122, 160). It also binds to Prdm16, stimulating expression of brown and beige adipocyte-selective genes (144).…”

Section: Genetic and Epigenetic Regulation Of Brown And Beige Fat Thementioning

confidence: 99%

Brown and Beige Adipose Tissues in Health and Disease

Rui

2017

Comprehensive Physiology

142

113

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Brown and beige adipocytes arise from distinct developmental origins. Brown adipose tissue (BAT) develops embryonically from precursors that also give to skeletal muscle. Beige fat develops postnatally and is highly inducible. Beige fat recruitment is mediated by multiple mechanisms, including de novo beige adipogenesis and white-to-brown adipocyte transdifferentiaiton. Beige precursors reside around vasculatures, and proliferate and differentiate into beige adipocytes. PDGFRα+Ebf2+ precursors are restricted to beige lineage cells, while another PDGFRα+ subset gives rise to beige adipocytes, white adipocytes, or fibrogenic cells. White adipocytes can be reprogramed and transdifferentiated into beige adipocytes. Brown and beige adipocytes display many similar properties, including multilocular lipid droplets, dense mitochondria, and expression of UCP1. UCP1-mediated thermogenesis is a hallmark of brown/beige adipocytes, albeit UCP1-independent thermogenesis also occurs. Development, maintenance, and activation of BAT/beige fat are guided by genetic and epigenetic programs. Numerous transcriptional factors and coactivators act coordinately to promote BAT/beige fat thermogenesis. Epigenetic reprograming also influences expression of brown/beige adipocyte-selective genes. BAT/beige fat is regulated by neuronal, hormonal, and immune mechanisms. Hypothalamic thermal circuits define the temperature setpoint that guides BAT/beige fat activity. Metabolic hormones, paracrine/autocrine factors, and various immune cells also play a critical role in regulating BAT/beige fat functions. BAT and beige fat defend temperature homeostasis, and regulate body weight and glucose and lipid metabolism. Obesity is associated with brown/beige fat deficiency, and reactivation of brown/beige fat provides metabolic health benefits in some patients. Pharmacological activation of BAT/beige fat may hold promise for combating metabolic diseases.

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Section: Genetic and Epigenetic Regulation Of Brown And Beige Fat Thementioning

confidence: 99%

Brown and Beige Adipose Tissues in Health and Disease

Rui

2017

Comprehensive Physiology

142

113

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“…42) and thus induce "browning". Sometimes this explanation for published browning effects is recognized (25,26,57), but often it is not.…”

Section: E209mentioning

confidence: 99%

“…Afterward, the temperature in the chambers was raised to 33°C and gradually decreased every second hour via 30, 27, 20, and 15°C to 5-8°C. In studies 3 and 5, the mice were allowed to adapt for 1 h at 30°C, and afterward the temperature was gradually decreased every 1.5 h from 30°C via 25,20,15, and 10°C to 5-8°C. In study 4, the mice were allowed to adapt overnight at 21°C.…”

Section: Indirect Calorimetrymentioning

confidence: 99%

No insulating effect of obesity

Fischer

Csikasz

Essen

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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The development of obesity may be aggravated if obesity itself insulates against heat loss and thus diminishes the amount of food burnt for body temperature control. This would be particularly important under normal laboratory conditions where mice experience a chronic cold stress (at Ϸ20°C). We used Scholander plots (energy expenditure plotted against ambient temperature) to examine the insulation (thermal conductance) of mice, defined as the inverse of the slope of the Scholander curve at subthermoneutral temperatures. We verified the method by demonstrating that shaved mice possessed only half the insulation of nonshaved mice. We examined a series of obesity models [mice fed high-fat diets and kept at different temperatures, classical diet-induced obese mice, ob/ob mice, and obesity-prone (C57BL/6) vs. obesityresistant (129S) mice]. We found that neither acclimation temperature nor any kind or degree of obesity affected the thermal insulation of the mice when analyzed at the whole mouse level or as energy expenditure per lean weight. Calculation per body weight erroneously implied increased insulation in obese mice. We conclude that, in contrast to what would be expected, obesity of any kind does not increase thermal insulation in mice, and therefore, it does not in itself aggravate the development of obesity. It may be discussed as to what degree of effect excess adipose tissue has on insulation in humans and especially whether significant metabolic effects are associated with insulation in humans. obesity; insulation; ob/ob DESPITE THE PRESENT INTEREST IN METABOLISM in connection with the global obesity epidemic, there is little knowledge concerning the extent to which obesity as such affects metabolism. There is widespread interest in issues such as the release of adipokines from adipose tissue depots, but many basic issues, such as the ability of adipose tissue to affect metabolism physically, have been little examined. One of these issues is the question of the ability of adipose tissue to function as a thermal insulation barrier, decreasing the heat loss from the organism and in this way decreasing the amount of energy needed to keep the organism warm, thereby increasing the amount of excess energy prone to storage in the form of (additional) fat.Whether an insulating effect of obesity exists is of significance both for humans and for animal models of obesity. However, with regard to experimental animals, the issue of insulation is of further interest. This is because most metabolic experiments are conducted with mice kept under conditions (standard laboratory conditions of Ϸ21°C) that are principally cold for the mouse (10,19,27,37,38,42,44) and thus where a high proportion of total metabolism (nearly half) is devoted to counteracting the resulting heat loss. This is a condition very different from that which is relevant for the metabolic physiology of most humans (living in a thermoneutral environment). Thus, under the current experimental conditions for mice, an insulating effect of increasing obesit...

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“…The roles of NRDC in transcriptional regulation were illustrated by the interaction of NRDC with various nuclear proteins such as histone deacetylase 3, peroxisome proliferator-activated receptor gamma coactivator 1-α and islet1. [43][44][45] Intriguingly, the nuclear function of NRDC is crucially involved in adaptive thermogenesis 44 and insulin secretion in vivo. 43 Although we cannot exclude a possible involvement of nuclear NRDC in AAIA, we demonstrate here that mRNA levels of TNF-α and ADAM17 in macrophages are not affected by the inhibition of NRDC, suggesting that it is extracellular NRDC that mainly regulates AAIA.…”

Section: Discussionmentioning

confidence: 99%

Nardilysin is involved in autoimmune arthritis via the regulation of tumour necrosis factor alpha secretion

et al. 2017

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ObjectiveTumour necrosis factor alpha (TNF-α) plays an important role in rheumatoid arthritis (RA). TNF-α is synthesised as a membrane-anchored precursor and is fully activated by a disintegrin and metalloproteinase 17 (ADAM17)-mediated ectodomain shedding. Nardilysin (NRDC) facilitates ectodomain shedding via activation of ADAM17. This study was undertaken to elucidate the role of NRDC in RA.MethodsNRDC-deficient (Nrdc–/–) mice and macrophage-specific NRDC-deficient (NrdcdelM) mice were examined in murine RA models, collagen antibody-induced arthritis (CAIA) and K/BxN serum transfer arthritis (K/BxN STA). We evaluated the effect of gene deletion or silencing of Nrdc on ectodomain shedding of TNF-α in macrophages or monocytes. NRDC concentration in synovial fluid from patients with RA and osteoarthritis (OA) were measured. We also examined whether local gene silencing of Nrdc ameliorated CAIA.ResultsCAIA and K/BxN STA were significantly attenuated in Nrdc–/– mice and NrdcdelM mice. Gene deletion or silencing of Nrdc in macrophages or THP-1 cells resulted in the reduction of TNF-α shedding. The level of NRDC is higher in synovial fluid from RA patients compared with that from OA patients. Intra-articular injection of anti-Nrdcsmall interfering RNA ameliorated CAIA.ConclusionThese data indicate that NRDC plays crucial roles in the pathogenesis of autoimmune arthritis and could be a new therapeutic target for RA treatment.

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Critical roles of nardilysin in the maintenance of body temperature homoeostasis

Cited by 36 publications

References 47 publications

Brown and Beige Adipose Tissues in Health and Disease

Brown and Beige Adipose Tissues in Health and Disease

No insulating effect of obesity

Nardilysin is involved in autoimmune arthritis via the regulation of tumour necrosis factor alpha secretion

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