Activation of Hypothalamic AMP-Activated Protein Kinase Ameliorates Metabolic Complications of Experimental Arthritis.
Journal
Arthritis & rheumatology (Hoboken, N.J.)
ISSN: 2326-5205
Titre abrégé: Arthritis Rheumatol
Pays: United States
ID NLM: 101623795
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
revised:
09
07
2021
received:
26
10
2020
accepted:
10
08
2021
pubmed:
17
8
2021
medline:
19
2
2022
entrez:
16
8
2021
Statut:
ppublish
Résumé
To investigate whether thermogenesis and the hypothalamus may be involved in the physiopathology of experimental arthritis (EA). EA was induced in male Lewis rats by intradermal injection of Freund's complete adjuvant (CFA). Food intake, body weight, plasma cytokines, thermographic analysis, gene and protein expression of thermogenic markers in brown adipose tissue (BAT) and white adipose tissue (WAT), and hypothalamic AMP-activated protein kinase (AMPK) were analyzed. Virogenetic activation of hypothalamic AMPK was performed. We first demonstrated that EA was associated with increased BAT thermogenesis and browning of subcutaneous WAT leading to elevated energy expenditure. Moreover, rats experiencing EA showed inhibition of hypothalamic AMPK, a canonical energy sensor modulating energy homeostasis at the central level. Notably, specific genetic activation of AMPK in the ventromedial nucleus of the hypothalamus (a key site modulating energy metabolism) reversed the effect of EA on energy balance, brown fat, and browning, as well as promoting amelioration of synovial inflammation in experimental arthritis. Overall, these data indicate that EA promotes a central catabolic state that can be targeted and reversed by the activation of hypothalamic AMPK. This might provide new therapeutic alternatives to treat rheumatoid arthritis (RA)-associated metabolic comorbidities, improving the overall prognosis in patients with RA.
Substances chimiques
AMP-Activated Protein Kinases
EC 2.7.11.31
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
212-222Informations de copyright
© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.
Références
Kerekes G, Nurmohamed MT, Gonzalez-Gay MA, Seres I, Paragh G, Kardos Z, et al. Rheumatoid arthritis and metabolic syndrome [review]. Nat Rev Rheumatol 2014;10:691-6.
Abella V, Scotece M, Conde J, Pino J, Gonzalez-Gay MA, Gomez-Reino JJ, et al. Leptin in the interplay of inflammation, metabolism and immune system disorders [review]. Nat Rev Rheumatol 2017;13:100-9.
Chen Z, Bozec A, Ramming A, Schett G. Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis [review]. Nat Rev Rheumatol 2019;15:9-17.
Arshad A, Rashid R, Benjamin K. The effect of disease activity on fat-free mass and resting energy expenditure in patients with rheumatoid arthritis versus noninflammatory arthropathies/soft tissue rheumatism. Mod Rheumatol 2007;17:470-5.
Conde J, Scotece M, Lopez V, Gomez R, Lago F, Pino J, et al. Adipokines: novel players in rheumatic diseases [review]. Discov Med 2013;15:73-83.
Procaccini C, Pucino V, Mantzoros CS, Matarese G. Leptin in autoimmune diseases [review]. Metabolism 2015;64:92-104.
La Cava A. Leptin in inflammation and autoimmunity [review]. Cytokine 2017;98:51-8.
Sattar N, McInnes IB. Rheumatoid arthritis: debunking the obesity-mortality paradox in RA. Nat Rev Rheumatol 2015;11:445-6.
George MD, Baker JF. The obesity epidemic and consequences for rheumatoid arthritis care [review]. Curr Rheumatol Rep 2016;18:6.
Procaccini C, Carbone F, Galgani M, La Rocca C, De Rosa V, Cassano S, et al. Obesity and susceptibility to autoimmune diseases [review]. Expert Rev Clin Immunol 2011;7:287-94.
Thomson TM, Lescarbeau RM, Drubin DA, Laifenfeld D, de Graaf D, Fryburg DA, et al. Blood-based identification of non-responders to anti-TNF therapy in rheumatoid arthritis. BMC Med Genomics 2015;8:26.
Tournadre A, Pereira B, Dutheil F, Giraud C, Courteix D, Sapin V, et al. Changes in body composition and metabolic profile during interleukin 6 inhibition in rheumatoid arthritis. J Cachexia Sarcopenia Muscle 2017;8:639-46.
Otero M, Nogueiras R, Lago F, Dieguez C, Gomez-Reino JJ, Gualillo O. Chronic inflammation modulates ghrelin levels in humans and rats. Rheumatology (Oxford) 2004;43:306-10.
Cutolo M, Foppiani L, Minuto F. Hypothalamic-pituitary-adrenal axis impairment in the pathogenesis of rheumatoid arthritis and polymyalgia rheumatica. J Endocrinol Invest 2002;25 l:19-23.
Stofkova A, Haluzik M, Zelezna B, Kiss A, Skurlova M, Lacinova Z, et al. Enhanced expressions of mRNA for neuropeptide Y and interleukin 1 β in hypothalamic arcuate nuclei during adjuvant arthritis-induced anorexia in Lewis rats. Neuroimmunomodulation 2009;16:377-84.
Skurlova M, Stofkova A, Kiss A, Belacek J, Pecha O, Deykun K, et al. Transient anorexia, hyper-nociception and cognitive impairment in early adjuvant arthritis in rats. Endocr Regul 2010;44:165-73.
Chikanza IC, Petrou P, Chrousos G. Perturbations of arginine vasopressin secretion during inflammatory stress: pathophysiologic implications [review]. Ann N Y Acad Sci 2000;917:825-34.
Bassi GS, Dias DP, Franchin M, Talbot J, Reis DG, Menezes GB, et al. Modulation of experimental arthritis by vagal sensory and central brain stimulation. Brain Behav Immun 2017;64:330-43.
López M, Nogueiras R, Tena-Sempere M, Diéguez C. Hypothalamic AMPK: a canonical regulator of whole-body energy balance [review]. Nat Rev Endocrinol 2016;12:421-32.
López M. AMPK wars: the VMH strikes back, return of the PVH. Trends Endocrinol Metab 2018;29:135-7.
López M, Varela L, Vázquez MJ, Rodríguez-Cuenca S, González CR, Velagapudi VR, et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 2010;16:1001-8.
Martins L, Seoane-Collazo P, Contreras C, González-García I, Martínez-Sánchez N, González F, et al. A functional link between AMPK and orexin mediates the effect of BMP8B on energy balance. Cell Rep 2016;16:2231-42.
Martínez-Sánchez N, Seoane-Collazo P, Contreras C, Varela L, Villarroya J, Rial-Pensado E, et al. Hypothalamic AMPK-ER stress-JNK1 axis mediates the central actions of thyroid hormones on energy balance. Cell Metab 2017;26:212-29.
Seoane-Collazo P, Roa J, Rial-Pensado E, Liñares-Pose L, Beiroa D, Ruíz-Pino F, et al. SF1-Specific AMPKα1 deletion protects against diet-induced obesity. Diabetes 2018;67:2213-26.
Villarroya F, Cereijo R, Villarroya J, Gavaldà-Navarro A, Giralt M. Toward an understanding of how immune cells control brown and beige adipobiology [review]. Cell Metab 2018;27:954-61.
Shabalina IG, Petrovic N, de Jong JM, Kalinovich AV, Cannon B, Nedergaard J. UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic. Cell Rep 2013;5:1196-203.
López M, Lage R, Saha AK, Pérez-Tilve D, Vázquez MJ, Varela L, et al. Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metab 2008;7:389-99.
Metsios GS, Stavropoulos-Kalinoglou A, Douglas KM, Koutedakis Y, Nevill AM, Panoulas VF, et al. Blockade of tumour necrosis factor-α in rheumatoid arthritis: effects on components of rheumatoid cachexia. Rheumatology (Oxford) 2007;46:1824-7.
Binymin K, Herrick A, Carlson G, Hopkins S. The effect of disease activity on body composition and resting energy expenditure in patients with rheumatoid arthritis. J Inflamm Res 2011;4:61-6.
Brooks SL, Neville AM, Rothwell NJ, Stock MJ, Wilson S. Sympathetic activation of brown-adipose-tissue thermogenesis in cachexia. Biosci Rep 1981;1:509-17.
Shellock FG, Riedinger MS, Fishbein MC. Brown adipose tissue in cancer patients: possible cause of cancer-induced cachexia. J Cancer Res Clin Oncol 1986;111:82-5.
Bing C, Brown M, King P, Collins P, Tisdale MJ, Williams G. Increased gene expression of brown fat uncoupling protein (UCP)1 and skeletal muscle UCP2 and UCP3 in MAC16-induced cancer cachexia. Cancer Res 2000;60:2405-10.
Tsoli M, Moore M, Burg D, Painter A, Taylor R, Lockie SH, et al. Activation of thermogenesis in brown adipose tissue and dysregulated lipid metabolism associated with cancer cachexia in mice. Cancer Res 2012;72:4372-82.
Muscaritoli M, Anker SD, Argiles J, Aversa Z, Bauer JM, Biolo G, et al. Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) "cachexia-anorexia in chronic wasting diseases" and "nutrition in geriatrics." Clin Nutr 2010;29:154-9.
Petruzzelli M, Schweiger M, Schreiber R, Campos-Olivas R, Tsoli M, Allen J, et al. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab 2014;20:433-47.
McCarthy N. Cachexia: running on empty [review]. Nat Rev Cancer 2014;14:576.
Argilés JM, Stemmler B, López-Soriano FJ, Busquets S. Inter-tissue communication in cancer cachexia [review]. Nat Rev Endocrinol 2018;15:9-20.
Masuko K. Rheumatoid cachexia revisited: a metabolic co-morbidity in rheumatoid arthritis [review]. Front Nutr 2014;1:20.
Santo RC, Fernandes KZ, Lora PS, Filippin LI, Xavier RM. Prevalence of rheumatoid cachexia in rheumatoid arthritis: a systematic review and meta-analysis. J Cachexia Sarcopenia Muscle 2018;9:816-25.
Claret M, Smith MA, Batterham RL, Selman C, Choudhury AI, Fryer LG, et al. AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J Clin Invest 2007;117:2325-36.
Janig W, Green PG. Acute inflammation in the joint: its control by the sympathetic nervous system and by neuroendocrine systems [review]. Auton Neurosci 2014;182:42-54.
Wiberg M, Widenfalk B. Involvement of connections between the brainstem and the sympathetic ganglia in the pathogenesis of rheumatoid arthritis: an anatomical study in rats. Scand J Plast Reconstr Surg Hand Surg 1993;27:269-76.
Tanaka H, Ueta Y, Yamashita U, Kannan H, Yamashita H. Biphasic changes in behavioral, endocrine, and sympathetic systems in adjuvant arthritis in Lewis rats. Brain Res Bull 1996;39:33-7.
Lorton D, Lubahn C, Lindquist CA, Schaller J, Washington C, Bellinger DL. Changes in the density and distribution of sympathetic nerves in spleens from Lewis rats with adjuvant-induced arthritis suggest that an injury and sprouting response occurs. J Comp Neurol 2005;489:260-73.
Lorton D, Lubahn C, Sweeney S, Major A, Lindquist CA, Schaller J, et al. Differences in the injury/sprouting response of splenic noradrenergic nerves in Lewis rats with adjuvant-induced arthritis compared with rats treated with 6-hydroxydopamine. Brain Behav Immun 2009;23:276-85.
Cano G, Passerin AM, Schiltz JC, Card JP, Morrison SF, Sved AF. Anatomical substrates for the central control of sympathetic outflow to interscapular adipose tissue during cold exposure. J Comp Neurol 2003;460:303-26.
Morrison SF, Madden CJ, Tupone D. Central neural regulation of brown adipose tissue thermogenesis and energy expenditure [review]. Cell Metab 2014;19:741-56.
Lin TT, Sung YL, Syu JY, Lin KY, Hsu HJ, Liao MT, et al. Anti-inflammatory and antiarrhythmic effects of beta-blocker in a rat model of rheumatoid arthritis. J Am Heart Assoc 2020;9:e016084.
Kang KY, Kim YK, Yi H, Kim J, Jung HR, Kim IJ, et al. Metformin downregulates Th17 cells differentiation and attenuates murine autoimmune arthritis. Int Immunopharmacol 2013;16:85-92.
Son HJ, Lee J, Lee SY, Kim EK, Park MJ, Kim KW, et al. Metformin attenuates experimental autoimmune arthritis through reciprocal regulation of Th17/Treg balance and osteoclastogenesis. Mediators Inflamm 2014;2014:973986.