Endocrine pathway of thermogenesis may provide therapeutic target for obesity

Irisin and FGF21 Are Cold-Induced Endocrine Activators of Brown Fat Function in Humans

Literature - Lee P et al., Cell Metab. 2014 - Cell Metab. 2014 Feb 4;19(2):302-9

Lee P, Linderman JD, Smith S et al.
Cell Metab. 2014 Feb 4;19(2):302-9. doi: 10.1016/j.cmet.2013.12.017


Cold-induced thermogenesis (CIT) is the response of the body to produce heat when ambient temperature drops.  First nonshivering thermogenesis (NST) is employed and when heat demand is not met, shivering thermogenesis (ST) is activated, generating heat from muscle contractions.
Long-term cold exposure reduces shivering, which seems to be a result of an enhanced NST response due to cold acclimatization [1].
In rodents, NST is mainly mediated by brown adipose tissue (BAT). Cold-activated BAT in humans is now receiving renewed attention, and BAT may indeed play a regulatory role in NST. BAT has also received attention because it may be exploited for weight control in obesity [2]. Indeed, activated BAT may contribute up to 20% of CIT following mild cold exposure [3], thus it may impact the long-term energy balance. Identification of endocrine activators of BAT could yield new therapeutic strategies for obesity [4].
Irisin is an exercise-induced myokine that reverses diet-induced obesity and diabetes by stimulating thermogenesis in rodents by increasing the number of brown adipocyte-like cells within white fat [5,6]. The paradox that exercise increases secretion of a thermogenic hormone may be explained by the hypothesis that this mechanism originated in the shivering-related muscle contraction. This study tests the hypothesis that NST is increased through BAT expansion, by studying the impact of cold exposure in healthy adults on irisin secretion.

Main results

  • Exercise increased serum irisin levels about threefold in healthy adults. The effect was stronger after submaximal than after maximal exercise.
  • Upon cold exposure, skin temperature decreased, while core temperature was stable. Arm-to-hand, skin-to-core, and supraclavicular-to-chest temperature gradients increased, indicative of vasoconstrictive, insulative and thermogenic responses, respectively. Energy expenditure increased, implying a CIT response.
  • Increased shivering activity was measured with surface electromyography (EMG). Individuals responded differently to cold exposure, as shivering activity ranged from 13% go 88%. Of all CIT components, irisin changes correlated the strongest with shivering (r=0.91, P<0.001): thus, irisin levels rose in those who shivered.
    The increase in irisin levels was similar as a result of cold exposure and exercise.
  • Lower levels of FGF21, a brown adipokine related to shivering-induced irisin secretion, was (non-significantly) associated with more intensive shivering. Lower FGF21 secretion indicates a lower NST response, which leads to increased heat generation via ST. Subjects with BAT had more FGF21 than BAT-negative subjects, suggesting that BAT is a source of FGF21.
  • In vitro, the bioenergetic profiles of human adipocytes (derived from neck fat; a region enriched in beige adipocytes) could be altered towards BAT and beige gene expression profiles by treatment with FNDC5 (irisin precursor) and FGF21.
  • Norepineprine-exposure to adipocytes mimics cold exposure in vitro. Adipocyte heat production was increased after FNDC5-treatment, which further increased after norepinephrine. FGF21 only increased heat production after norepinephrine.
  • The FNDC5/FGF21 experiments were repeated in human subcutaneous and visceral adipocytes, to get insight on the generalisability of the heat production results. BAT-like thermogenic response only increased in subcutaneous adipocytes, and to a lesser extent than in neck adipocytes.


These data suggest that exercise-induced irisin secretion could have evolved from shivering-related muscle contraction, in an attempt to increase brown fat thermogenesis and FGF levels. In vitro experiments provide mechanistic insight into the in vivo observations, in that shivering-stimulated irisin, together with FGF21, may transform white adipocytes into BAT-like cells, thereby increasing thermogenic capacity.
The natural human tendency for thermal comfort limits cold exposure these days. Irisin and FGF21 may represent endocrine mimics of these thermogenic stimuli that be exploitable as a therapeutic target to attain weight control and improve overall metabolic profile.

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1. Davis, T.R. (1961). Chamber cold acclimatization in man. J. Appl. Physiol. 16, 1011–1015.
2. Yoneshiro, T., Aita, S., Matsushita, M., et al. (2013). Recruited brown adipose tissue as an antiobesity agent in humans. J. Clin. Invest. 123, 3404–3408.
3. Chen, K.Y., Brychta, R.J., Linderman, J.D.,et al. (2013). Brown fat activation mediates cold-induced thermogenesis in adult humans in response to a mild decrease in ambient temperature. J. Clin. Endocrinol. Metab. 98, E1218–E1223
4. Lee, P., Swarbrick, M.M., and Ho, K.K. (2013). Brown adipose tissue in adult humans: a metabolic renaissance. Endocr. Rev. 34, 413–438.
5. Petrovic, N., Walden, T.B., Shabalina, I.G., et al.  (2010). Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J. Biol. Chem. 285, 7153–7164.
6. Wu, J., Bostrom, P., Sparks, L.M., et al. (2012). Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150, 366–376.

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