Chemokine receptors on the defensive – the surprising role of CXCR4 in brown adipose tissue

Longbiao Yao, Janet Heuser-Baker, Jana Barlic-Dicen


Obesity, which is triggered by over-nutrition and supported by the excessive expansion of adipose tissue due to hyperplasia and hypertrophy, has been linked to an increased incidence of type 2 diabetes, hypertension, cardiovascular disease and cancer. Since obesity-induced co-morbidities impose a significant financial burden on healthcare systems in Western societies, clear understanding of molecules and mechanisms supporting physiologic and pathologic activities of adipose tissue is mandatory. Abundant evidence shows that development of obesity is facilitated by a low-grade inflammation fueled by infiltration of pro-inflammatory leukocytes into white adipose tissue pads, which is in part mediated by chemokines and chemokine receptors.  However, not all members of the chemokine system facilitate development of obesity. In this publication we highlight a surprising role of CXCR4 in fat cells where this chemokine receptor promotes energy expenditure and prevents excessive inflammatory leukocyte recruitment into adipose tissue, and by so doing, limits obesity.

Full Text:



Giralt M, Villarroya F. White, brown, beige/brite: different adipose cells for different functions? Endocrinology 2013;154: 2992-3000.

Guo S. Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models to disease mechanisms. J Endocrinol 2014; 220:T1-T23.

Hariri N, Thibault L. High-fat diet-induced obesity in animal models. Nutr Res Rev 2010;23:270-299.

Scroyen I, Hemmeryckx B, Lijnen HR. From mice to men - mouse models in obesity research: what can we learn? Thromb and Haemost2013;110:634-640.

Sun S, Ji Y, Kersten S, Qi L. Mechanisms of inflammatory responses in obese adipose tissue. Annu Rev Nutr 2012;32: 261-286.

Chawla A, Nguyen KD, Goh YP. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 2011;11: 738-749.

Talukdar S, Oh DY, Bandyopadhyay G, Li D, Xu J, McNelis J, et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med 2012;18:1407-1412.

Liu J, Divoux A, Sun J, Zhang J, Clement K, Glickman JN, et al. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med 2009; 15:940-945.

Wu D, Molofsky AB, Liang HE, Ricardo-Gonzalez RR, Jouihan HA, Bando JK, et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 2011;332:243-247.

Sell H, Habich C, Eckel J. Adaptive immunity in obesity and insulin resistance. Nat Rev Endocrinol 2012;8:709-716.

DeFuria J, Belkina AC, Jagannathan-Bogdan M, Snyder-Cappione J, Carr JD, Nersesova YR, et al. B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile. Proc Natl Acad Sci U S A 2013;110:5133-5138.

Bachelerie F, Ben-Baruch A, Burkhardt AM, Combadiere C, Farber JM, Graham GJ, et al. International union of pharmacology. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacol Rev 2014;66:1-79.

Anderson EK, Gutierrez DA, Hasty AH. Adipose tissue recruitment of leukocytes. Curr Opin Lipidol 2010;21:172-177.

Surmi BK, Hasty AH. The role of chemokines in recruitment of immune cells to the artery wall and adipose tissue. Vascul Pharmacol 2010;52:27-36.

Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa Ki, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006;116:1494-1505.

Oh DY, Morinaga H, Talukdar S, Bae EJ, Olefsky JM. Increased macrophage migration into adipose tissue in obese mice. Diabetes 2012;61:346-354.

Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 2006;116:115-124.

Kamei N, Tobe K, Suzuki R, Ohsugi M, Watanabe T, Kubota N, et al. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem 2006;281:26602-26614.

Inouye KE, Shi H, Howard JK, Daly CH, Lord GM, Rollins BJ, et al. Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue. Diabetes 2007;56:2242-2250.

Neels JG, Badeanlou L, Hester KD, Samad F. Keratinocyte-derived chemokine in obesity: expression, regulation, and role in adipose macrophage infiltration and glucose homeostasis. J Biol Chem 2009;28:20692-20698.

Kitade H, Sawamoto K, Nagashimada M, Inoue H, Yamamoto Y, Sai Y, et al. CCR5 Plays a critical role in obesity-induced adipose tissue inflammation and insulin resistance by regulating both macrophage recruitment and M1/M2 status. Diabetes 2012;61: 1680-1690.

Kennedy A, Webb CD, Hill AA, Gruen ML, Jackson LG, Hasty AH. Loss of CCR5 results in glucose intolerance in diet-induced obese mice. Am J Physiol Endocrinol Metab 2013;305: E897-E906.

Oberlin E, Amara A, Bachelerie F, Bessia C, Virelizier JL, Arenzana-Seisdedos F, et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 1996;382:833-835.

Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa Si, Kitamura Y, et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 1996;382:635-638.

Tachibana K, Hirota S, Iizasa H, Yoshida H, Kawabata K, Kataoka Y, et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 1998;393: 591-594.

Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 1998;393:595-599.

Nagasawa T. CXC chemokine ligand 12 (CXCL12) and its receptor CXCR4. J Mol Med 2014;92:433-439.

Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 2006;25: 977-988.

Tzeng YS, Li H, Kang YL, Chen WC, Cheng WC, Lai DM. Loss of Cxcl12/Sdf-1 in adult mice decreases the quiescent state of hematopoietic stem/progenitor cells and alters the pattern of hematopoietic regeneration after myelosuppression. Blood 2010; 117:429-439.

Ding L, Morrison SJ. Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 2013;495:231-235.

Chatterjee S, Behnam Azad B, Nimmagadda S. The intricate role of CXCR4 in cancer. Adv Cancer Res 2014; 124:31-82.

Yao L, Heuser-Baker J, Herlea-Pana O, Zhang N, Szweda LI, Griffin TM, et al. Deficiency in adipocyte chemokine receptor CXCR4 exacerbates obesity and compromises thermoregulatory responses of brown adipose tissue in a mouse model of diet-induced obesity. FASEB J 2014;28:4534-4550.

Virtue S, Vidal-Puig A. Assessment of brown adipose tissue function. Front Physiol 2013;4:128.



  • There are currently no refbacks.

Copyright (c) 2014 Longbiao Yao, Janet Heuser-Baker, Jana Barlic-Dicen

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.