早產兒支氣管肺發育不全（俗稱早產兒慢性肺疾病）目前仍是新生兒科領域中最具挑戰性的議題之一。出生後給予全身性類固醇是少數被證實可以有效治療或預防早產兒肺支氣管發育不全的治療。棕色脂肪在新生兒體溫調控中扮演無法取代的重要角色，尤其是在剛出生的前幾天。除了產熱，棕色脂肪也參與能量的代謝，因此在治療肥胖和糖尿病的領域上得到許多關注。解偶聯蛋白1 (Uncoupling protein-1, UCP1) 是棕色脂肪中最重要的產熱蛋白。在成鼠的實驗中，類固醇已經被證明會抑制解偶聯蛋白1的表現量。在臨床研究中也觀察到接受類固醇治療的早產兒會有體重成長遲滯的狀況。我們推測投與全身性類固醇可能會干擾新生兒的能量代謝和棕色脂肪的產熱作用。實驗設計如下：新生幼鼠從出生後第一天開始，連續三天每天接受腹腔內施打dexamethasone (Dex)或是食鹽水，第四天分析Dex對於棕色脂肪的影響，包括產熱功能、脂肪的代謝、粒線體的型態及呼吸功能和自嗜作用。我們發現Dex會導致幼鼠生長遲滯、棕色脂肪白化 、解偶聯蛋白1的表現量下降以及不耐寒冷。Dex會造成棕色脂肪中粒線體的傷害，使粒線體失去正常的形狀和cristae排列。粒線體的呼吸功能也受到抑制，包括粒線體的最大呼吸量(maximal respiration)、閒置能力(spare capacity)和解偶聯呼吸(proton leak或uncoupling respiration)都受到影響，並且程度上和Dex的劑量呈現正比關係。棕色脂肪中的Cpt1a基因，轉譯粒線體脂肪酸氧化作用的限速酶基因，也會受到Dex影響而抑制其表現量。粒線體的融合作用大於分裂作用 (粒線體融合蛋白OPA1和MFN2表現量上升，分裂蛋白DRP1、FIS1和p-MFF表現量下降)，使得粒線體的形狀普遍拉長。Dex會增加自嗜小體的合成但同時卻影響其代謝清除。不管是使用CQ嘗試阻擋自嗜作用的進行，或是使用rapamycin加速自嗜作用都無法挽救Dex對於棕色脂肪造成的傷害。我們發現AMPK活化劑AICAR可以部分挽救Dex造成的棕色脂肪傷害，包括改善棕色脂肪白化與及體溫的維持，並且讓粒線體的型態回復到比較正常的外觀。這結果顯示AICAR的作用機轉不只是活化自嗜作用的啟動，也同時促進粒線體的分裂，因此加強了自嗜流(autophagy flux)，如此得以減緩Dex對於新生幼鼠棕色脂肪的損傷。

Bronchopulmonary dysplasia (BPD) (previously known as chronic lung disease of prematurity) remains one of the greatest challenges in the field of neonatology. Postnatal systemic corticosteroids are one of the few proven effective treatments for prevention and treatment of BPD. BAT plays an indispensable role in temperature regulation in neonates, especially during the first days of life. Beyond thermogenesis, BAT also plays an important role in energy metabolism and has received much attention in treating obesity and diabetes. Uncoupling protein-1 (UCP1) is the key thermogenic protein in BAT. Corticosteroids were shown to inhibit the expression of UCP1 in adult rodents. Clinical studies also demonstrated that preterm infants receiving corticosteroid treatment had reduced weight gain during the treatment. We speculated that systemic corticosteroid therapy may disrupt normal energy expenditure and BAT thermogenesis in neonates. Our experimental design was as follows: neonatal rats were given either three consecutive doses of intraperitoneal injection of dexamethasone (Dex) (0.2 mg/kg/day) or saline from postnatal P1 to P3. We investigated the effects of Dex on BAT including thermogenesis, lipid metabolism, BAT mitochondrial dynamics, respiratory function and autophagy flux on P4. We found that postnatal Dex treatment induced growth retardation, BAT whitening, UCP1 downregulation and cold intolerance in neonatal rats. BAT mitochondria were damaged, evident by loss of normal number, structure, and alignment of cristae. Mitochondrial respiration, including maximal respiration, spare capacity and proton leak (uncoupling respiration), were suppressed after Dex administration, in a dose-dependent manner. The mRNA expression of Cpt1a, which encodes for the first rate-limiting enzyme of mitochondrial fatty acid oxidation, was decreased after Dex treatment. Mitochondrial fission-fusion balance was disrupted and skewed toward increased fusion, reflected by increased OPA1 and MFN2 and decreased DRP1, FIS1 and phosphorylated MFF protein levels. Autophagosome synthesis was increased but clearance was partially impaired. Autophagy modulators, including chloroquine and rapamycin, both failed to rescue Dex-induced BAT dysfunction. Last but not least, we demonstrated the therapeutic potential of AMPK activator AICAR, which could partially rescue BAT whitening and cold intolerance and restored BAT mitochondrial morphology. These results showed that AICAR not only activated autophagy initiation but also promoted mitochondrial fission, therefore augmenting autophagy flux and thus capable of alleviating Dex-mediated BAT dysfunction in neonatal rat pups.

1 Doyle, L. W., Cheong, J. L., Ehrenkranz, R. A. & Halliday, H. L. Early (< 8 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev 10, Cd001146, doi:10.1002/14651858.CD001146.pub5 (2017).
2 CANNON, B. & NEDERGAARD, J. Brown Adipose Tissue: Function and Physiological Significance. Physiological reviews 84, 277-359, doi:10.1152/physrev.00015.2003 (2004).
3 Lyon, A. J., Pikaar, M. E., Badger, P. & McIntosh, N. Temperature control in very low birthweight infants during first five days of life. Archives of disease in childhood. Fetal and neonatal edition 76, F47-50, doi:10.1136/fn.76.1.f47 (1997).
4 Knobel, R. B., Holditch-Davis, D., Schwartz, T. A. & Wimmer, J. E., Jr. Extremely low birth weight preterm infants lack vasomotor response in relationship to cold body temperatures at birth. Journal of perinatology : official journal of the California Perinatal Association 29, 814-821, doi:10.1038/jp.2009.99 (2009).
5 Celi, F. S. Brown adipose tissue--when it pays to be inefficient. The New England journal of medicine 360, 1553-1556, doi:10.1056/NEJMe0900466 (2009).
6 Lowell, B. B. & Spiegelman, B. M. Towards a molecular understanding of adaptive thermogenesis. Nature 404, 652-660, doi:10.1038/35007527 (2000).
7 Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961-967, doi:10.1038/nature07182 (2008).
8 Timmons, J. A. et al. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proceedings of the National Academy of Sciences of the United States of America 104, 4401-4406, doi:10.1073/pnas.0610615104 (2007).
9 Dawkins, M. J. & Hull, D. The production of heat by fat. Scientific American 213, 62-69 (1965).
10 Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. The New England journal of medicine 360, 1509-1517, doi:10.1056/NEJMoa0810780 (2009).
11 van Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. The New England journal of medicine 360, 1500-1508, doi:10.1056/NEJMoa0808718 (2009).
12 Ouellet, V. et al. Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans. The Journal of Clinical Endocrinology & Metabolism 96, 192-199 (2011).
13 Lee, P., Greenfield, J. R., Ho, K. K. & Fulham, M. J. A critical appraisal of the prevalence and metabolic significance of brown adipose tissue in adult humans. American journal of physiology. Endocrinology and metabolism 299, E601-606, doi:10.1152/ajpendo.00298.2010 (2010).
14 Stanford, K. I. et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. The Journal of clinical investigation 123, 215-223, doi:10.1172/jci62308 (2013).
15 Liu, X. et al. Brown adipose tissue transplantation improves whole-body energy metabolism. Cell research 23, 851-854, doi:10.1038/cr.2013.64 (2013).
16 Liu, X. et al. Brown Adipose Tissue Transplantation Reverses Obesity in Ob/Ob Mice. Endocrinology 156, 2461-2469, doi:10.1210/en.2014-1598 (2015).
17 Loh, R. K. C., Kingwell, B. A. & Carey, A. L. Human brown adipose tissue as a target for obesity management; beyond cold-induced thermogenesis. Obesity reviews : an official journal of the International Association for the Study of Obesity 18, 1227-1242, doi:10.1111/obr.12584 (2017).
18 Yeh, T. F. et al. Early dexamethasone therapy in preterm infants: a follow-up study. Pediatrics 101, E7 (1998).
19 Murphy, B. P. et al. Impaired cerebral cortical gray matter growth after treatment with dexamethasone for neonatal chronic lung disease. Pediatrics 107, 217-221 (2001).
20 Yoder, B. A., Harrison, M. & Clark, R. H. Time-related changes in steroid use and bronchopulmonary dysplasia in preterm infants. Pediatrics 124, 673-679, doi:10.1542/peds.2008-2793 (2009).
21 Doyle, L. W., Halliday, H. L., Ehrenkranz, R. A., Davis, P. G. & Sinclair, J. C. An update on the impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk of bronchopulmonary dysplasia. The Journal of pediatrics 165, 1258-1260, doi:10.1016/j.jpeds.2014.07.049 (2014).
22 Parikh, N. A. et al. Perinatal Risk and Protective Factors in the Development of Diffuse White Matter Abnormality on Term-Equivalent Age Magnetic Resonance Imaging in Infants Born Very Preterm. The Journal of pediatrics 233, 58-65.e53, doi:10.1016/j.jpeds.2020.11.058 (2021).
23 Kline, J. E., Illapani, V. S. P., He, L., Altaye, M. & Parikh, N. A. Retinopathy of Prematurity and Bronchopulmonary Dysplasia are Independent Antecedents of Cortical Maturational Abnormalities in Very Preterm Infants. Scientific reports 9, 19679, doi:10.1038/s41598-019-56298-x (2019).
24 Sweet, D. G. et al. European Consensus Guidelines on the Management of Respiratory Distress Syndrome - 2019 Update. Neonatology 115, 432-450, doi:10.1159/000499361 (2019).
25 Halliday, H. L. Update on Postnatal Steroids. Neonatology 111, 415-422, doi:10.1159/000458460 (2017).
26 Doyle, L. W., Davis, P. G., Morley, C. J., McPhee, A. & Carlin, J. B. Low-dose dexamethasone facilitates extubation among chronically ventilator-dependent infants: a multicenter, international, randomized, controlled trial. Pediatrics 117, 75-83, doi:10.1542/peds.2004-2843 (2006).
27 Nuytten, A. et al. Postnatal Corticosteroids Policy for Very Preterm Infants and Bronchopulmonary Dysplasia. Neonatology 117, 308-315, doi:10.1159/000507195 (2020).
28 Ramaswamy, V. V. et al. Assessment of Postnatal Corticosteroids for the Prevention of Bronchopulmonary Dysplasia in Preterm Neonates: A Systematic Review and Network Meta-analysis. JAMA pediatrics 175, e206826-e206826, doi:10.1001/jamapediatrics.2020.6826 (2021).
29 Klaus, S., Ely, M., Encke, D. & Heldmaier, G. Functional assessment of white and brown adipocyte development and energy metabolism in cell culture. Dissociation of terminal differentiation and thermogenesis in brown adipocytes. Journal of cell science 108 ( Pt 10), 3171-3180 (1995).
30 Wang, X. et al. Evaluation and optimization of differentiation conditions for human primary brown adipocytes. Scientific reports 8, 5304, doi:10.1038/s41598-018-23700-z (2018).
31 Barclay, J. L. et al. Effects of glucocorticoids on human brown adipocytes. The Journal of endocrinology 224, 139-147, doi:10.1530/joe-14-0538 (2015).
32 Hughes, K. A., Reynolds, R. M., Andrew, R., Critchley, H. O. & Walker, B. R. Glucocorticoids turn over slowly in human adipose tissue in vivo. The Journal of clinical endocrinology and metabolism 95, 4696-4702, doi:10.1210/jc.2010-0384 (2010).
33 Macfarlane, D. P., Forbes, S. & Walker, B. R. Glucocorticoids and fatty acid metabolism in humans: fuelling fat redistribution in the metabolic syndrome. The Journal of endocrinology 197, 189-204, doi:10.1677/joe-08-0054 (2008).
34 Oakley, R. H., Sar, M. & Cidlowski, J. A. The Human Glucocorticoid Receptor β Isoform: EXPRESSION, BIOCHEMICAL PROPERTIES, AND PUTATIVE FUNCTION (∗). Journal of Biological Chemistry 271, 9550-9559, doi:10.1074/jbc.271.16.9550 (1996).
35 FELDMAN, D. Evidence that Brown Adipose Tissue Is a Glucocorticoid Target Organ*. Endocrinology 103, 2091-2097, doi:10.1210/endo-103-6-2091 (1978).
36 Soumano, K. et al. Glucocorticoids inhibit the transcriptional response of the uncoupling protein-1 gene to adrenergic stimulation in a brown adipose cell line. Molecular and cellular endocrinology 165, 7-15, doi:10.1016/s0303-7207(00)00276-8 (2000).
37 van den Beukel, J. C. et al. Cold Exposure Partially Corrects Disturbances in Lipid Metabolism in a Male Mouse Model of Glucocorticoid Excess. Endocrinology 156, 4115-4128, doi:10.1210/en.2015-1092 (2015).
38 Moriscot, A., Rabelo, R. & Bianco, A. C. Corticosterone inhibits uncoupling protein gene expression in brown adipose tissue. The American journal of physiology 265, E81-87, doi:10.1152/ajpendo.1993.265.1.E81 (1993).
39 Poggioli, R. et al. Dexamethasone reduces energy expenditure and increases susceptibility to diet-induced obesity in mice. Obesity (Silver Spring, Md.) 21, E415-420, doi:10.1002/oby.20338 (2013).
40 Kong, X. et al. Glucocorticoids transcriptionally regulate miR-27b expression promoting body fat accumulation via suppressing the browning of white adipose tissue. Diabetes 64, 393-404, doi:10.2337/db14-0395 (2015).
41 Lv, Y. F. et al. Glucocorticoids Suppress the Browning of Adipose Tissue via miR-19b in Male Mice. Endocrinology 159, 310-322, doi:10.1210/en.2017-00566 (2018).
42 Liu, J. et al. Essential roles of 11β-HSD1 in regulating brown adipocyte function. Journal of Molecular Endocrinology 50, 103-113, doi:10.1530/jme-12-0099 (2013).
43 Doig, C. L. et al. 11β-HSD1 Modulates the Set Point of Brown Adipose Tissue Response to Glucocorticoids in Male Mice. Endocrinology 158, 1964-1976, doi:10.1210/en.2016-1722 (2017).
44 Djouadi, F. et al. Mitochondrial biogenesis and development of respiratory chain enzymes in kidney cells: role of glucocorticoids. The American journal of physiology 267, C245-254, doi:10.1152/ajpcell.1994.267.1.C245 (1994).
45 Weber, K. et al. Glucocorticoid hormone stimulates mitochondrial biogenesis specifically in skeletal muscle. Endocrinology 143, 177-184, doi:10.1210/endo.143.1.8600 (2002).
46 Shen, G. et al. Autophagy as a target for glucocorticoid-induced osteoporosis therapy. Cellular and molecular life sciences : CMLS 75, 2683-2693, doi:10.1007/s00018-018-2776-1 (2018).
47 Psarra, A. M. et al. Glucocorticoid receptor isoforms in human hepatocarcinoma HepG2 and SaOS-2 osteosarcoma cells: presence of glucocorticoid receptor alpha in mitochondria and of glucocorticoid receptor beta in nucleoli. The international journal of biochemistry & cell biology 37, 2544-2558, doi:10.1016/j.biocel.2005.06.015 (2005).
48 Fujita, C. et al. Direct effects of corticosterone on ATP production by mitochondria from immortalized hypothalamic GT1-7 neurons. The Journal of steroid biochemistry and molecular biology 117, 50-55, doi:10.1016/j.jsbmb.2009.07.002 (2009).
49 Song, I. H. & Buttgereit, F. Non-genomic glucocorticoid effects to provide the basis for new drug developments. Molecular and cellular endocrinology 246, 142-146, doi:10.1016/j.mce.2005.11.012 (2006).
50 Du, J. et al. Dynamic regulation of mitochondrial function by glucocorticoids. Proceedings of the National Academy of Sciences of the United States of America 106, 3543-3548, doi:10.1073/pnas.0812671106 (2009).
51 Hernandez-Alvarez, M. I. et al. Glucocorticoid modulation of mitochondrial function in hepatoma cells requires the mitochondrial fission protein Drp1. Antioxidants & redox signaling 19, 366-378, doi:10.1089/ars.2011.4269 (2013).
52 Deng, J. et al. Autophagy inhibition prevents glucocorticoid-increased adiposity via suppressing BAT whitening. Autophagy, 1-15, doi:10.1080/15548627.2019.1628537 (2019).
53 Mottillo, E. P. et al. Lack of Adipocyte AMPK Exacerbates Insulin Resistance and Hepatic Steatosis through Brown and Beige Adipose Tissue Function. Cell metabolism 24, 118-129, doi:10.1016/j.cmet.2016.06.006 (2016).
54 Ramage, L. E. et al. Glucocorticoids Acutely Increase Brown Adipose Tissue Activity in Humans, Revealing Species-Specific Differences in UCP-1 Regulation. Cell metabolism 24, 130-141, doi:10.1016/j.cmet.2016.06.011 (2016).
55 Thuzar, M. et al. Glucocorticoids suppress brown adipose tissue function in humans: A double-blind placebo-controlled study. Diabetes, obesity & metabolism 20, 840-848, doi:10.1111/dom.13157 (2018).
56 Wang, Y. C., Huang, C. C. & Hsu, K. S. The role of growth retardation in lasting effects of neonatal dexamethasone treatment on hippocampal synaptic function. PloS one 5, e12806, doi:10.1371/journal.pone.0012806 (2010).
57 Shrivastava, A., Lyon, A. & McIntosh, N. The effect of dexamethasone on growth, mineral balance and bone mineralisation in preterm infants with chronic lung disease. European journal of pediatrics 159, 380-384, doi:10.1007/s004310051291 (2000).
58 Chen, Q. M. et al. Corticosteroids inhibit cell death induced by doxorubicin in cardiomyocytes: induction of antiapoptosis, antioxidant, and detoxification genes. Molecular pharmacology 67, 1861-1873, doi:10.1124/mol.104.003814 (2005).
59 Semple, B. D., Blomgren, K., Gimlin, K., Ferriero, D. M. & Noble-Haeusslein, L. J. Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Progress in neurobiology 106-107, 1-16, doi:10.1016/j.pneurobio.2013.04.001 (2013).
60 Clubb, F. J., Jr. & Bishop, S. P. Formation of binucleated myocardial cells in the neonatal rat. An index for growth hypertrophy. Lab Invest 50, 571-577 (1984).
61 Li, F., Wang, X., Capasso, J. M. & Gerdes, A. M. Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development. J Mol Cell Cardiol 28, 1737-1746, doi:10.1006/jmcc.1996.0163 (1996).
62 Hagberg, H., Bona, E., Gilland, E. & Puka-Sundvall, M. Hypoxia-ischaemia model in the 7-day-old rat: possibilities and shortcomings. Acta Paediatr Suppl 422, 85-88 (1997).
63 Sze, C. I. et al. The role of glucocorticoid receptors in dexamethasone-induced apoptosis of neuroprogenitor cells in the hippocampus of rat pups. Mediators of inflammation 2013, 628094, doi:10.1155/2013/628094 (2013).
64 Yates, H. L. & Newell, S. J. Minidex: very low dose dexamethasone (0.05 mg/kg/day) in chronic lung disease. Archives of disease in childhood. Fetal and neonatal edition 96, F190-194, doi:10.1136/adc.2010.187203 (2011).
65 Nair, A. B. & Jacob, S. A simple practice guide for dose conversion between animals and human. Journal of basic and clinical pharmacy 7, 27-31, doi:10.4103/0976-0105.177703 (2016).
66 Stier, A. et al. Mitochondrial uncoupling prevents cold-induced oxidative stress: a case study using UCP1 knockout mice. The Journal of experimental biology 217, 624-630, doi:10.1242/jeb.092700 (2014).
67 Hershko, A. & Ciechanover, A. The ubiquitin system. Annual review of biochemistry 67, 425-479 (1998).
68 Wang, X., Wei, D., Song, Z., Jiao, H. & Lin, H. Effects of fatty acid treatments on the dexamethasone-induced intramuscular lipid accumulation in chickens. PloS one 7, e36663, doi:10.1371/journal.pone.0036663 (2012).
69 Wang, Y. X. et al. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 113, 159-170, doi:10.1016/s0092-8674(03)00269-1 (2003).
70 Kamei, Y. et al. PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity. Proceedings of the National Academy of Sciences of the United States of America 100, 12378-12383, doi:10.1073/pnas.2135217100 (2003).
71 Lu, Y. et al. Mitophagy is required for brown adipose tissue mitochondrial homeostasis during cold challenge. Scientific reports 8, 8251, doi:10.1038/s41598-018-26394-5 (2018).
72 Chen, Y. et al. Dihydromyricetin protects against liver ischemia/reperfusion induced apoptosis via activation of FOXO3a-mediated autophagy. Oncotarget 7, 76508-76522, doi:10.18632/oncotarget.12894 (2016).
73 Lamoureux, F. et al. Blocked autophagy using lysosomotropic agents sensitizes resistant prostate tumor cells to the novel Akt inhibitor AZD5363. Clinical cancer research : an official journal of the American Association for Cancer Research 19, 833-844, doi:10.1158/1078-0432.Ccr-12-3114 (2013).
74 Zhao, X. G. et al. Chloroquine-enhanced efficacy of cisplatin in the treatment of hypopharyngeal carcinoma in xenograft mice. PloS one 10, e0126147, doi:10.1371/journal.pone.0126147 (2015).
75 Long, L. et al. Chloroquine prevents progression of experimental pulmonary hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type II receptor degradation. Circulation research 112, 1159-1170, doi:10.1161/circresaha.111.300483 (2013).
76 Rubinsztein, D. C. et al. In search of an "autophagomometer". Autophagy 5, 585-589, doi:10.4161/auto.5.5.8823 (2009).
77 Lin, N. Y. et al. Inactivation of autophagy ameliorates glucocorticoid-induced and ovariectomy-induced bone loss. Annals of the rheumatic diseases 75, 1203-1210, doi:10.1136/annrheumdis-2015-207240 (2016).
78 Vyas, A. R. et al. Chemoprevention of prostate cancer by d,l-sulforaphane is augmented by pharmacological inhibition of autophagy. Cancer research 73, 5985-5995, doi:10.1158/0008-5472.Can-13-0755 (2013).
79 Martinez-Castellanos, M. A. et al. Long-term effect of antiangiogenic therapy for retinopathy of prematurity up to 5 years of follow-up. Retina (Philadelphia, Pa.) 33, 329-338, doi:10.1097/IAE.0b013e318275394a (2013).
80 Xia, X. et al. Glucocorticoid-induced autophagy in osteocytes. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 25, 2479-2488, doi:10.1002/jbmr.160 (2010).
81 Grander, D., Kharaziha, P., Laane, E., Pokrovskaja, K. & Panaretakis, T. Autophagy as the main means of cytotoxicity by glucocorticoids in hematological malignancies. Autophagy 5, 1198-1200, doi:10.4161/auto.5.8.10122 (2009).
82 Troncoso, R. et al. Dexamethasone-induced autophagy mediates muscle atrophy through mitochondrial clearance. Cell cycle (Georgetown, Tex.) 13, 2281-2295, doi:10.4161/cc.29272 (2014).
83 Singh, R. et al. Autophagy regulates adipose mass and differentiation in mice. The Journal of clinical investigation 119, 3329-3339, doi:10.1172/jci39228 (2009).
84 Zhang, Y. et al. Adipose-specific deletion of autophagy-related gene 7 (atg7) in mice reveals a role in adipogenesis. Proceedings of the National Academy of Sciences of the United States of America 106, 19860-19865, doi:10.1073/pnas.0906048106 (2009).
85 Altshuler-Keylin, S. et al. Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance. Cell metabolism 24, 402-419, doi:10.1016/j.cmet.2016.08.002 (2016).
86 Mizushima, N. & Komatsu, M. Autophagy: renovation of cells and tissues. Cell 147, 728-741, doi:10.1016/j.cell.2011.10.026 (2011).
87 Vizza, D. et al. Rapamycin-induced autophagy protects proximal tubular renal cells against proteinuric damage through the transcriptional activation of the nerve growth factor receptor NGFR. Autophagy 14, 1028-1042, doi:10.1080/15548627.2018.1448740 (2018).
88 Abdellatif, M., Sedej, S., Carmona-Gutierrez, D., Madeo, F. & Kroemer, G. Autophagy in Cardiovascular Aging. Circulation research 123, 803-824, doi:10.1161/circresaha.118.312208 (2018).
89 van den Beukel, J. C. et al. Direct activating effects of adrenocorticotropic hormone (ACTH) on brown adipose tissue are attenuated by corticosterone. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 28, 4857-4867, doi:10.1096/fj.14-254839 (2014).
90 Tondera, D. et al. SLP-2 is required for stress-induced mitochondrial hyperfusion. The EMBO journal 28, 1589-1600, doi:10.1038/emboj.2009.89 (2009).
91 Lebeau, J. et al. The PERK Arm of the Unfolded Protein Response Regulates Mitochondrial Morphology during Acute Endoplasmic Reticulum Stress. Cell reports 22, 2827-2836, doi:10.1016/j.celrep.2018.02.055 (2018).
92 Wang, X., Lin, H., Song, Z. & Jiao, H. Dexamethasone facilitates lipid accumulation and mild feed restriction improves fatty acids oxidation in skeletal muscle of broiler chicks (Gallus gallus domesticus). Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 151, 447-454, doi:10.1016/j.cbpc.2010.01.010 (2010).
93 Wang, X. J., Song, Z. G., Jiao, H. C. & Lin, H. Skeletal muscle fatty acids shift from oxidation to storage upon dexamethasone treatment in chickens. General and comparative endocrinology 179, 319-330, doi:10.1016/j.ygcen.2012.09.013 (2012).
94 Ivy, J. R. et al. Glucocorticoids regulate mitochondrial fatty acid oxidation in fetal cardiomyocytes. The Journal of physiology 599, 4901-4924, doi:10.1113/jp281860 (2021).
95 Gospodarska, E., Nowialis, P. & Kozak, L. P. Mitochondrial turnover: a phenotype distinguishing brown adipocytes from interscapular brown adipose tissue and white adipose tissue. The Journal of biological chemistry 290, 8243-8255, doi:10.1074/jbc.M115.637785 (2015).
96 Chia, L. Y. et al. Adrenoceptor regulation of the mechanistic target of rapamycin in muscle and adipose tissue. British journal of pharmacology 176, 2433-2448, doi:10.1111/bph.14616 (2019).
97 Betz, C. & Hall, M. N. Where is mTOR and what is it doing there? The Journal of cell biology 203, 563-574, doi:10.1083/jcb.201306041 (2013).
98 Labbé, S. M. et al. mTORC1 is Required for Brown Adipose Tissue Recruitment and Metabolic Adaptation to Cold. Scientific reports 6, 37223, doi:10.1038/srep37223 (2016).
99 Liu, D. et al. Activation of mTORC1 is essential for β-adrenergic stimulation of adipose browning. The Journal of clinical investigation 126, 1704-1716, doi:10.1172/jci83532 (2016).
100 Minard, A. Y. et al. mTORC1 Is a Major Regulatory Node in the FGF21 Signaling Network in Adipocytes. Cell reports 17, 29-36, doi:10.1016/j.celrep.2016.08.086 (2016).
101 Contreras, C. et al. The brain and brown fat. Annals of medicine 47, 150-168, doi:10.3109/07853890.2014.919727 (2015).
102 van der Vaart, J. I., Boon, M. R. & Houtkooper, R. H. The Role of AMPK Signaling in Brown Adipose Tissue Activation. Cells 10, 1122, doi:10.3390/cells10051122 (2021).
103 Tanida, M., Yamamoto, N., Shibamoto, T. & Rahmouni, K. Involvement of hypothalamic AMP-activated protein kinase in leptin-induced sympathetic nerve activation. PloS one 8, e56660, doi:10.1371/journal.pone.0056660 (2013).
104 López, M., Nogueiras, R., Tena-Sempere, M. & Diéguez, C. Hypothalamic AMPK: a canonical regulator of whole-body energy balance. Nature reviews. Endocrinology 12, 421-432, doi:10.1038/nrendo.2016.67 (2016).
105 López, M. et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nature medicine 16, 1001-1008, doi:10.1038/nm.2207 (2010).
106 López, M. Hypothalamic AMPK and energy balance. European journal of clinical investigation 48, e12996, doi:10.1111/eci.12996 (2018).
107 Martínez de Morentin, P. B. et al. Nicotine induces negative energy balance through hypothalamic AMP-activated protein kinase. Diabetes 61, 807-817, doi:10.2337/db11-1079 (2012).
108 Jin, J. et al. Metformin protects cells from mutant huntingtin toxicity through activation of AMPK and modulation of mitochondrial dynamics. Neuromolecular medicine 18, 581-592 (2016).
109 Łabuzek, K. et al. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacological Reports 62, 956-965 (2010).
110 Marangos, P. et al. Adenosinergic modulation of homocysteine‐induced seizures in mice. Epilepsia 31, 239-246 (1990).
111 Chen, Y. T. et al. Excessive Glucocorticoids During Pregnancy Impair Fetal Brown Fat Development and Predispose Offspring to Metabolic Dysfunctions. Diabetes 69, 1662-1674, doi:10.2337/db20-0009 (2020).
112 Bancalari, E. & Jain, D. Bronchopulmonary Dysplasia: 50 Years after the Original Description. Neonatology 115, 384-391, doi:10.1159/000497422 (2019).
113 Feng, Y., Kumar, P., Wang, J. & Bhatt, A. J. Dexamethasone but not the equivalent doses of hydrocortisone induces neurotoxicity in neonatal rat brain. Pediatric research 77, 618-624, doi:10.1038/pr.2015.19 (2015).
114 Baud, O. et al. Association Between Early Low-Dose Hydrocortisone Therapy in Extremely Preterm Neonates and Neurodevelopmental Outcomes at 2 Years of Age. Jama 317, 1329-1337, doi:10.1001/jama.2017.2692 (2017).