Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Clinical Studies and Practice

Investigating the effects of Orexin-A on thermogenesis in human deep neck brown adipose tissue

International Journal of Obesity volume 41, pages 1646–1653 (2017)Cite this article

Subjects

Abstract

Background:

Despite successful preclinical testing, 85% of early clinical trials for novel drugs fail. Most futilities originate from molecular mechanisms of the drug(s) tested. It is critically important to develop validated human cell-based model systems in which animal-based research can be translated in order to complement the preclinical in vivo findings prior to implementation of a clinical trial. Obesity is associated with reduced circulating levels of Orexin-A (OX-A) in humans. OX-A increases thermogenesis in rodent brown adipose tissue (AT), yet this phenomenon has not been explored in humans.

Methods:

We established a cell-based model system of human brown and white adipocytes and tested the effects of OX-A on thermogenesis.

Results:

Contrary to published in vivo and in vitro reports in rodents, OX-A treatment alone or in combination with an adrenergic stimulus did neither enhance thermogenesis nor its related transcriptional program in a human in vitro model of brown adipocytes or AT explants.

Conclusions:

Translating preclinical findings in human model systems poses a challenge that must be overcome for the development of effective therapeutic compounds and targets.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. de Lecea L, Huerta R . Hypocretin (orexin) regulation of sleep-to-wake transitions. Front Pharmacol 2014; 5: 16.

    Article  Google Scholar 

  2. Kotz C, Nixon J, Butterick T, Perez-Leighton C, Teske J, Billington C . Brain orexin promotes obesity resistance. Ann NY Acad Sci 2012; 1264: 72–86.

    Article  CAS  Google Scholar 

  3. Mahler SV, Smith RJ, Moorman DE, Sartor GC, Aston-Jones G . Multiple roles for orexin/hypocretin in addiction. Prog Brain Res 2012; 198: 79–121.

    Article  CAS  Google Scholar 

  4. Teske JA, Billington CJ, Kotz CM . Mechanisms underlying obesity resistance associated with high spontaneous physical activity. Neuroscience 2014; 256: 91–100.

    Article  CAS  Google Scholar 

  5. Ammoun S, Holmqvist T, Shariatmadari R, Oonk HB, Detheux M, Parmentier M et al. Distinct recognition of OX1 and OX2 receptors by orexin peptides. J Pharmacol Exp Ther 2003; 305: 507–514.

    Article  CAS  Google Scholar 

  6. Sellayah D, Bharaj P, Sikder D . Orexin is required for brown adipose tissue development, differentiation, and function. Cell Metab 2011; 14: 478–490.

    Article  CAS  Google Scholar 

  7. Balasko M, Szelenyi Z, Szekely M . Central thermoregulatory effects of neuropeptide Y and orexin A in rats. Acta Physiol Hung 1999; 86: 219–222.

    CAS  PubMed  Google Scholar 

  8. Yoshimichi G, Yoshimatsu H, Masaki T, Sakata T . Orexin-A regulates body temperature in coordination with arousal status. Exp Biol Med (Maywood) 2001; 226: 468–476.

    Article  CAS  Google Scholar 

  9. Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 2001; 30: 345–354.

    Article  CAS  Google Scholar 

  10. Funato H, Tsai AL, Willie JT, Kisanuki Y, Williams SC, Sakurai T et al. Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity. Cell Metab 2009; 9: 64–76.

    Article  CAS  Google Scholar 

  11. Sellayah D, Sikder D . Orexin receptor-1 mediates brown fat developmental differentiation. Adipocyte 2012; 1: 58–63.

    Article  CAS  Google Scholar 

  12. Adam JA, Menheere PP, van Dielen FM, Soeters PB, Buurman WA, Greve JW . Decreased plasma orexin-A levels in obese individuals. Int J Obes Relat Metab Disord 2002; 26: 274–276.

    Article  CAS  Google Scholar 

  13. Nishino S, Ripley B, Overeem S, Nevsimalova S, Lammers GJ, Vankova J et al. Low cerebrospinal fluid hypocretin (Orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol 2001; 50: 381–388.

    Article  CAS  Google Scholar 

  14. Bronsky J, Nedvidkova J, Zamrazilova H, Pechova M, Chada M, Kotaska K et al. Dynamic changes of orexin A and leptin in obese children during body weight reduction. Physiol Res 2007; 56: 89–96.

    CAS  PubMed  Google Scholar 

  15. Digby JE, Chen J, Tang JY, Lehnert H, Matthews RN, Randeva HS . Orexin receptor expression in human adipose tissue: effects of orexin-A and orexin-B. J Endocrinol 2006; 191: 129–136.

    Article  CAS  Google Scholar 

  16. Jespersen NZ, Larsen TJ, Peijs L, Daugaard S, Homoe P, Loft A et al. A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans. Cell Metab 2013; 17: 798–805.

    Article  CAS  Google Scholar 

  17. Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012; 150: 366–376.

    Article  CAS  Google Scholar 

  18. Hanssen MJ, van der Lans AA, Brans B, Hoeks J, Jardon KM, Schaart G et al. Short-term cold acclimation recruits brown adipose tissue in obese humans. Diabetes 2016; 65: 1179–1189.

    Article  CAS  Google Scholar 

  19. Hanssen MJ, Wierts R, Hoeks J, Gemmink A, Brans B, Mottaghy FM et al. Glucose uptake in human brown adipose tissue is impaired upon fasting-induced insulin resistance. Diabetologia 2015; 58: 586–595.

    Article  CAS  Google Scholar 

  20. Gibb S . Toxicity testing in the 21st century: a vision and a strategy. Reprod Toxicol 2008; 25: 136–138.

    Article  CAS  Google Scholar 

  21. Mak IW, Evaniew N, Ghert M . Lost in translation: animal models and clinical trials in cancer treatment. Am J Transl Res 2014; 6: 114–118.

    PubMed  PubMed Central  Google Scholar 

  22. Bogacka I, Xie H, Bray GA, Smith SR . Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 2005; 54: 1392–1399.

    Article  CAS  Google Scholar 

  23. Sparks LM, Ukropcova B, Smith J, Pasarica M, Hymel D, Xie H et al. Relation of adipose tissue to metabolic flexibility. Diabetes Res Clin Pract 2009; 83: 32–43.

    Article  CAS  Google Scholar 

  24. Lee MJ, Wu Y, Fried SK . A modified protocol to maximize differentiation of human preadipocytes and improve metabolic phenotypes. Obesity (Silver Spring) 2012; 20: 2334–2340.

    Article  CAS  Google Scholar 

  25. Skrzypski M, T Le T, Kaczmarek P, Pruszynska-Oszmalek E, Pietrzak P, Szczepankiewicz D et al. Orexin A stimulates glucose uptake, lipid accumulation and adiponectin secretion from 3T3-L1 adipocytes and isolated primary rat adipocytes. Diabetologia 2011; 54: 1841–1852.

    Article  CAS  Google Scholar 

  26. Shen Y, Zhao Y, Zheng D, Chang X, Ju S, Guo L . Effects of orexin A on GLUT4 expression and lipid content via MAPK signaling in 3T3-L1 adipocytes. J Steroid Biochem Mol Biol 2013; 138: 376–383.

    Article  CAS  Google Scholar 

  27. Yu G, Floyd ZE, Wu X, Hebert T, Halvorsen YD, Buehrer BM et al. Adipogenic differentiation of adipose-derived stem cells. Methods Mol Biol 2011; 702: 193–200.

    Article  CAS  Google Scholar 

  28. Tews D, Schwar V, Scheithauer M, Weber T, Fromme T, Klingenspor M et al. Comparative gene array analysis of progenitor cells from human paired deep neck and subcutaneous adipose tissue. Mol Cell Endocrinol 2014; 395: 41–50.

    Article  CAS  Google Scholar 

  29. Bortolotto JW, Margis R, Ferreira AC, Padoin AV, Mottin CC, Guaragna RM . Adipose tissue distribution and quantification of PPARbeta/delta and PPARgamma1-3 mRNAs: discordant gene expression in subcutaneous, retroperitoneal and visceral adipose tissue of morbidly obese patients. Obes Surg 2007; 17: 934–940.

    Article  Google Scholar 

  30. Betz MJ, Slawik M, Lidell ME, Osswald A, Heglind M, Nilsson D et al. Presence of brown adipocytes in retroperitoneal fat from patients with benign adrenal tumors: relationship with outdoor temperature. J Clin Endocrinol Metab 2013; 98: 4097–4104.

    Article  CAS  Google Scholar 

  31. Komolka K, Albrecht E, Wimmers K, Michal JJ, Maak S . Molecular heterogeneities of adipose depots—potential effects on adipose-muscle cross-talk in humans, mice and farm animals. J Genomics 2014; 2: 31–44.

    Article  Google Scholar 

  32. Cypess AM, White AP, Vernochet C, Schulz TJ, Xue R, Sass CA et al. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat Med 2013; 19: 635–639.

    Article  CAS  Google Scholar 

  33. Lee P, Swarbrick MM, Zhao JT, Ho KK . Inducible brown adipogenesis of supraclavicular fat in adult humans. Endocrinology 2011; 152: 3597–3602.

    Article  CAS  Google Scholar 

  34. Shinoda K, Luijten IH, Hasegawa Y, Hong H, Sonne SB, Kim M et al. Genetic and functional characterization of clonally derived adult human brown adipocytes. Nat Med 2015; 21: 389–394.

    Article  CAS  Google Scholar 

  35. Tupone D, Madden CJ, Cano G, Morrison SF . An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis. J Neurosci 2011; 31: 15944–15955.

    Article  CAS  Google Scholar 

  36. Bronsky J, Nedvidkova J, Krasnicanova H, Vesela M, Schmidtova J, Koutek J et al. Changes of orexin A plasma levels in girls with anorexia nervosa during eight weeks of realimentation. Int J Eat Disord 2011; 44: 547–552.

    Article  Google Scholar 

  37. Lafontan M, Barbe P, Galitzky J, Tavernier G, Langin D, Carpene C et al. Adrenergic regulation of adipocyte metabolism. Hum Reprod 1997; 12 (Suppl 1): 6–20.

    Article  CAS  Google Scholar 

  38. Chen J, Randeva HS . Genomic organization and regulation of the human orexin (hypocretin) receptor 2 gene: identification of alternative promoters. Biochem J 2010; 427: 377–390.

    Article  CAS  Google Scholar 

  39. Nedergaard J, Golozoubova V, Matthias A, Shabalina I, Ohba K, Ohlson K et al. Life without UCP1: mitochondrial, cellular and organismal characteristics of the UCP1-ablated mice. Biochem Soc Trans 2001; 29 (Pt 6): 756–763.

    Article  CAS  Google Scholar 

  40. Yehuda-Shnaidman E, Buehrer B, Pi J, Kumar N, Collins S . Acute stimulation of white adipocyte respiration by PKA-induced lipolysis. Diabetes 2010; 59: 2474–2483.

    Article  CAS  Google Scholar 

  41. Blondin DP, Frisch F, Phoenix S, Guerin B, Turcotte EE, Haman F et al. Inhibition of intracellular triglyceride lipolysis suppresses cold-induced brown adipose tissue metabolism and increases shivering in humans. Cell Metab 2017; 25: 438–447.

    Article  CAS  Google Scholar 

  42. DiMasi JA, Grabowski HG, Hansen RW . Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ 2016; 47: 20–33.

    Article  Google Scholar 

  43. Scannell JW, Blanckley A, Boldon H, Warrington B . Diagnosing the decline in pharmaceutical R&D efficiency. Nat Rev Drug Discov 2012; 11: 191–200.

    Article  CAS  Google Scholar 

  44. Sellayah D, Sikder D . Feeding the heat on brown fat. Ann NY Acad Sci 2013; 1302: 11–23.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the study volunteers and patients for their participation. This study was funded by an internal Strategic Protocol from the Translational Research Institute for Metabolism and Diabetes (no. TRI-SP-14-01) (to LMS).

Author contributions

Conceptualization, LMS and SRS; methodology, MFP, AD, AVS and LMS; investigation, MFP, AD, AVS and LMS; writing—original draft, LMS and MFP; writing—review and editing, MFP, AD, AVS, SRS and LMS; funding acquisition, LMS; resources, AVS, SRS and LMS; supervision, LMS.

Author information

Authors and Affiliations

  1. Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL, USA

    M F Pino, A Divoux, S R Smith & L M Sparks

  2. Center for Specialized Surgery, Florida Hospital, Orlando, FL, USA

    A V Simmonds

  3. Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL, USA

    S R Smith & L M Sparks

Authors
  1. M F Pino
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Divoux
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A V Simmonds
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S R Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L M Sparks
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L M Sparks.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on International Journal of Obesity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pino, M., Divoux, A., Simmonds, A. et al. Investigating the effects of Orexin-A on thermogenesis in human deep neck brown adipose tissue. Int J Obes 41, 1646–1653 (2017). https://doi.org/10.1038/ijo.2017.155

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2017.155

This article is cited by

Search

Advanced search

Quick links