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.

  • Review Article
  • Published:

Intermuscular adipose tissue in metabolic disease

Nature Reviews Endocrinology volume 19, pages 285–298 (2023)Cite this article

Subjects

Abstract

Intermuscular adipose tissue (IMAT) is a distinct adipose depot described in early reports as a ‘fatty replacement’ or ‘muscle fat infiltration’ that was linked to ageing and neuromuscular disease. Later studies quantifying IMAT with modern in vivo imaging methods (computed tomography and magnetic resonance imaging) revealed that IMAT is proportionately higher in men and women with type 2 diabetes mellitus and the metabolic syndrome than in people without these conditions and is associated with insulin resistance and poor physical function with ageing. In parallel, agricultural research has provided extensive insight into the role of IMAT and other muscle lipids in muscle (that is, meat) quality. In addition, studies using rodent models have shown that IMAT is a bona fide white adipose tissue depot capable of robust triglyceride storage and turnover. Insight into the importance of IMAT in human biology has been limited by the dearth of studies on its biological properties, that is, the quality of IMAT. However, in the past few years, investigations have begun to determine that IMAT has molecular and metabolic features that distinguish it from other adipose tissue depots. These studies will be critical to further decipher the role of IMAT in health and disease and to better understand its potential as a therapeutic target.

Key points

  • Intermuscular adipose tissue (IMAT) is a unique adipose depot that strongly associates with insulin resistance, type 2 diabetes mellitus and ageing.

  • Quantitatively, IMAT comprises a fairly small proportion of total body adipose and subcutaneous adipose tissue, although the amount of IMAT in the total body can be similar to the amount of abdominal visceral adipose tissue.

  • The molecular, cellular and other biological properties of IMAT are only beginning to be appreciated and understood.

  • IMAT has at least three distinct cellular origins.

  • Access to human IMAT samples through biopsies, combined with the latest molecular biology methods of transcriptomics, proteomics (such as single-cell or single-nuclei sequencing) and secretome (exosomes) analyses, will be critical to better understand the role of this distinct adipose tissue in human health and disease.

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

Fig. 1: Micrograph depicting human IMAT in erector spinae muscle in a patient with spinal stenosis.
Fig. 2: Magnetic resonance images.
Fig. 3: Whole-body magnetic resonance imaging.
Fig. 4: Schematic with proposed mechanisms, secretome, adipokines and non-adipocyte cells that underlie the biological properties of IMAT with metabolic disease.

Similar content being viewed by others

References

  1. Goodpaster, B. H., Thaete, F. L. & Kelley, D. E. Thigh adipose tissue distribution is associated with insulin resistance in obesity and in type 2 diabetes mellitus. Am. J. Clin. Nutr. 71, 885–892 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Goodpaster, B. H. & Kelley, D. E. Skeletal muscle triglyceride: marker or mediator of obesity-induced insulin resistance in type 2 diabetes mellitus? Curr. Diabetes Rep. 2, 216–222 (2002).

    Article  Google Scholar 

  3. Machann, J., Häring, H., Schick, F. & Stumvoll, M. Intramyocellular lipids and insulin resistance. Diabetes Obes. Metab. 6, 239–248 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. De Feyter, H. M. et al. Increased intramyocellular lipid content but normal skeletal muscle mitochondrial oxidative capacity throughout the pathogenesis of type 2 diabetes. FASEB J. 22, 3947–3955 (2008).

    Article  PubMed  Google Scholar 

  5. Luzi, L. et al. Intramyocellular lipid accumulation and reduced whole body lipid oxidation in HIV lipodystrophy. Am. J. Physiol. Endocrinol. Metab. 284, E274–E280 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Nakagawa, Y. et al. Age-related changes in intramyocellular lipid in humans by in vivo 1H-MR spectroscopy. Gerontology 53, 218–223 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Correa-de-Araujo, R. et al. Myosteatosis in the context of skeletal muscle function deficit: an interdisciplinary workshop at the national institute on aging. Front. Physiol. 11, 963 (2020).

    Article  PubMed Central  PubMed  Google Scholar 

  8. Nordal, H., Dietrichson, P., Eldevik, P. & Grønseth, K. Fat infiltration, atrophy and hypertrophy of skeletal muscles demonstrated by X‐ray computed tomography in neurological patients. Acta Neurol. Scand. 77, 115–122 (1988).

    Article  CAS  PubMed  Google Scholar 

  9. Rossi, A. et al. Quantification of intermuscular adipose tissue in the erector spinae muscle by MRI: agreement with histological evaluation. Obesity 18, 2379–2384 (2010).

    Article  PubMed  Google Scholar 

  10. Albrecht, E. et al. Cellular conditions for intramuscular fat deposition in Japanese Black and Holstein steers. Meat Sci. 89, 13–20 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Biltz, N. K. & Meyer, G. A. A novel method for the quantification of fatty infiltration in skeletal muscle. Skelet. Muscle 7, 1–13 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  12. Agarwal, A. K., Tunison, K., Mitsche, M. A., McDonald, J. G. & Garg, A. Insights into lipid accumulation in skeletal muscle in dysferlin-deficient mice. J. Lipid Res. 60, 2057–2073 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Biltz, N. K. et al. Infiltration of intramuscular adipose tissue impairs skeletal muscle contraction. J. Physiol. 598, 2669–2683 (2020).

    Article  CAS  PubMed  Google Scholar 

  14. Pagano, A. F. et al. Short‐term disuse promotes fatty acid infiltration into skeletal muscle. J. Cachexia Sarcopenia Muscle 9, 335–347 (2018).

    Article  PubMed  Google Scholar 

  15. Goodpaster, B. H. et al. Association between regional adipose tissue distribution and both type 2 diabetes and impaired glucose tolerance in elderly men and women. Diabetes Care 26, 372–379 (2003).

    Article  PubMed  Google Scholar 

  16. Gallagher, D. et al. Adipose tissue in muscle: a novel depot similar in size to visceral adipose tissue. Am. J. Clin. Nutr. 81, 903–910 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Hausman, G. J., Bergen, W. G., Etherton, T. D. & Smith, S. B. The history of adipocyte and adipose tissue research in meat animals. Anim. Sci. J. 96, 473–486 (2018).

    Article  Google Scholar 

  18. Sparks, L. M., Goodpaster, B. H. & Bergman, B. C. The metabolic significance of intermuscular adipose tissue: is IMAT a friend or a foe to metabolic health? Diabetes 70, 2457–2467 (2021).

    Article  CAS  PubMed  Google Scholar 

  19. Hausman, G. J. The origin and purpose of layers of subcutaneous adipose tissue in pigs and man. Horm. Mol. Biol. Clin. Investig. https://doi.org/10.1515/hmbci-2018-0001 (2018).

    Article  PubMed  Google Scholar 

  20. Bukowska, J. et al. The effect of hypoxia on the proteomic signature of pig adipose-derived stromal/stem cells (pASCs). Sci. Rep. 10, 20035 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Casado, J. G. et al. Comparative phenotypic and molecular characterization of porcine mesenchymal stem cells from different sources for translational studies in a large animal model. Vet. Immunol. Immunopathol. 147, 104–112 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Hart, E. A. et al. Lessons learned from the initial sequencing of the pig genome: comparative analysis of an 8 Mb region of pig chromosome 17. Genome Biol. 8, R168 (2007).

    Article  PubMed Central  PubMed  Google Scholar 

  23. Pant, S. D. et al. Comparative analyses of QTLs influencing obesity and metabolic phenotypes in pigs and humans. PLoS One 10, e0137356 (2015).

    Article  PubMed Central  PubMed  Google Scholar 

  24. Do, D. N. et al. Genome-wide association study reveals genetic architecture of eating behavior in pigs and its implications for humans obesity by comparative mapping. PLoS One 8, e71509 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Meurens, F., Summerfield, A., Nauwynck, H., Saif, L. & Gerdts, V. The pig: a model for human infectious diseases. Trends Microbiol. 20, 50–57 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. Houpt, K. A., Houpt, T. R. & Pond, W. G. The pig as a model for the study of obesity and of control of food intake: a review. Yale J. Biol. Med. 52, 307 (1979).

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Stenkula, K. G. & Erlanson-Albertsson, C. Adipose cell size: importance in health and disease. Am. J. Physiol. Regul. Integr. Comp. Physiol. 315, R284–R295 (2018).

    Article  CAS  PubMed  Google Scholar 

  28. Arner, P. & Spalding, K. L. Fat cell turnover in humans. Biochem. Biophys. Res. Commun. 396, 101–104 (2010).

    Article  CAS  PubMed  Google Scholar 

  29. Bong, J. J., Cho, K. K. & Baik, M. Comparison of gene expression profiling between bovine subcutaneous and intramuscular adipose tissues by serial analysis of gene expression. Cell Biol. Int. 34, 125–133 (2009).

    PubMed  Google Scholar 

  30. Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Mourot, J. & Kouba, M. Development of intra- and intermuscular adipose tissue in growing large white and Meishan pigs. Reprod. Nutr. Dev. 39, 125–132 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Bagchi, D. P. & MacDougald, O. A. Identification and dissection of diverse mouse adipose depots. J. Vis. Exp. 149, e59499 (2019).

    Google Scholar 

  33. Kirtland, J. & Gurr, M. I. Adipose tissue cellularity: a review. 2. The relationship between cellularity and obesity. Int. J. Obes. 3, 15–55 (1979).

    CAS  PubMed  Google Scholar 

  34. Mattacks, C. A., Sadler, D. & Pond, C. M. The effects of exercise and dietary restriction on the activities of hexokinase and phosphofructokinase in superficial, intra-abdominal and intermuscular adipose tissue of guinea-pigs. Comp. Biochem. Physiol. B 87, 533–542 (1987).

    Article  CAS  PubMed  Google Scholar 

  35. Kannan, R., Palmquist, D. L. & Baker, N. Contribution of intermuscular fat to lipogenesis from dietary glucose carbon in mice. Biochim. Biophys. Acta 431, 225–232 (1976).

    Article  CAS  PubMed  Google Scholar 

  36. Mattacks, C. A. & Pond, C. M. Site-specific and sex differences in the rates of fatty acid/triacylglycerol substrate cycling in adipose, tissue and muscle of sedentary and exercised dwarf hamsters (Phodopus sungorus). Int. J. Obes. 12, 585–597 (1988).

    CAS  PubMed  Google Scholar 

  37. Pond, C. M. & Mattacks, C. A. The effects of noradrenaline and insulin on lipolysis in adipocytes isolated from nine different adipose depots of guinea-pigs. Int. J. Obes. 15, 609–618 (1991).

    CAS  PubMed  Google Scholar 

  38. Goodpaster, B. H. & Sparks, L. M. Metabolic flexibility in health and disease. Cell Metab. 25, 1027–1036 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Amati, F. et al. Lower thigh subcutaneous and higher visceral abdominal adipose tissue content both contribute to insulin resistance. Obesity 20, 1115–1117 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Ross, R., Freeman, J., Hudson, R. & Janssen, I. Abdominal obesity, muscle composition, and insulin resistance in premenopausal women. J. Clin. Endocrinol. Metab. 87, 5044–5051 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Boettcher, M. et al. Intermuscular adipose tissue (IMAT): association with other adipose tissue compartments and insulin sensitivity. J. Magn. Reson. 29, 1340–1345 (2009).

    Google Scholar 

  42. Dubé, M. C. et al. The contribution of visceral adiposity and mid‐thigh fat‐rich muscle to the metabolic profile in postmenopausal women. Obesity 19, 953–959 (2011).

    Article  PubMed  Google Scholar 

  43. Goodpaster, B. H., Leland Thaete, F., Simoneau, J.-A. & Kelley, D. E. Subcutaneous abdominal fat and thigh muscle composition predict insulin sensitivity independently of visceral fat. Diabetes 46, 1579–1585 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Albu, J. B. et al. Independent association of insulin resistance with larger amounts of intermuscular adipose tissue and a greater acute insulin response to glucose in African American than in white nondiabetic women. Am. J. Clin. Nutr. 82, 1210–1217 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Kim, S.-K., Park, S., Hwang, I., Lee, Y. & Cho, Y.-W. High fat stores in ectopic compartments in men with newly diagnosed type 2 diabetes: an anthropometric determinant of carotid atherosclerosis and insulin resistance. Int. J. Obes. 34, 105–110 (2010).

    Article  CAS  Google Scholar 

  46. Kim, J. E. et al. Intermuscular adipose tissue content and intramyocellular lipid fatty acid saturation are associated with glucose homeostasis in middle-aged and older adults. Endocrinol. Metab. 32, 257–264 (2017).

    Article  CAS  Google Scholar 

  47. Ryan, A. & Nicklas, B. Age-related changes in fat deposition in mid-thigh muscle in women: relationships with metabolic cardiovascular disease risk factors. Int. J. Obes. 23, 126–132 (1999).

    Article  CAS  Google Scholar 

  48. Yim, J. et al. Intermuscular adipose tissue rivals visceral adipose tissue in independent associations with cardiovascular risk. Int. J. Obes. 31, 1400–1405 (2007).

    Article  CAS  Google Scholar 

  49. Yim, J.-E., Heshka, S., Albu, J. B., Heymsfield, S. & Gallagher, D. Femoral-gluteal subcutaneous and intermuscular adipose tissues have independent and opposing relationships with CVD risk. J. Appl. Physiol. 104, 700–707 (2008).

    Article  PubMed  Google Scholar 

  50. Zoico, E. et al. Adipose tissue infiltration in skeletal muscle of healthy elderly men: relationships with body composition, insulin resistance, and inflammation at the systemic and tissue level. J. Gerontol. Biol. Sci. Med. Sci. 65, 295–299 (2010).

    Article  Google Scholar 

  51. Therkelsen, K. E. et al. Intramuscular fat and associations with metabolic risk factors in the Framingham Heart Study. Arterioscler. Thromb. Vasc. Biol. 33, 863–870 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Miljkovic-Gacic, I. et al. Adipose tissue infiltration in skeletal muscle: age patterns and association with diabetes among men of African ancestry. Am. J. Clin. Nutr. 87, 1590–1595 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Visser, M. et al. Leg muscle mass and composition in relation to lower extremity performance in men and women aged 70 to 79: the health, aging and body composition study. J. Am. Geriatr. Soc. 50, 897–904 (2002).

    Article  PubMed  Google Scholar 

  54. Goodpaster, B. H. et al. Attenuation of skeletal muscle and strength in the elderly: the Health ABC study. J. Appl. Physiol. 90, 2157–2165 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Marcus, R. L. et al. Intramuscular adipose tissue, sarcopenia, and mobility function in older individuals. J. Aging Res. 2012, 629637 (2012).

    Article  PubMed Central  PubMed  Google Scholar 

  56. Delmonico, M. J. et al. Longitudinal study of muscle strength, quality, and adipose tissue infiltration. Am. J. Clin. Nutr. 90, 1579–1585 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Marcus, R. L., Addison, O., Kidde, J. P., Dibble, L. E. & Lastayo, P. C. Skeletal muscle fat infiltration: impact of age, inactivity, and exercise. J. Nutr. Health Aging 14, 362–366 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Song, M. Y. et al. Sarcopenia and increased adipose tissue infiltration of muscle in elderly African American women. Am. J. Clin. Nutr. 79, 874–880 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Addison, O., Marcus, R. L., Lastayo, P. C. & Ryan, A. S. Intermuscular fat: a review of the consequences and causes. Int. J. Endocrinol. 2014, 309570 (2014).

    Article  PubMed Central  PubMed  Google Scholar 

  60. Chambers, T. L. et al. Skeletal muscle size, function, and adiposity with lifelong aerobic exercise. J. Appl. Physiol. 128, 368–378 (2020).

    Article  CAS  PubMed  Google Scholar 

  61. Konopka, A. R., Wolff, C. A., Suer, M. K. & Harber, M. P. Relationship between intermuscular adipose tissue infiltration and myostatin before and after aerobic exercise training. Am. J. Physiol. Regul. Integr. Comp. Physiol. 315, R461–R468 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Durheim, M. T., Slentz, C. A., Bateman, L. A., Mabe, S. K. & Kraus, W. E. Relationships between exercise-induced reductions in thigh intermuscular adipose tissue, changes in lipoprotein particle size, and visceral adiposity. Am. J. Physiol. Endocrinol. Metab. 295, E407–E412 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Beasley, L. E. et al. Inflammation and race and gender differences in computerized tomography‐measured adipose depots. Obesity 17, 1062–1069 (2009).

    Article  PubMed  Google Scholar 

  64. Cartier, A. et al. Age-related differences in inflammatory markers in men: contribution of visceral adiposity. Metabolism 58, 1452–1458 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Koster, A. et al. Body fat distribution and inflammation among obese older adults with and without metabolic syndrome. Obesity 18, 2354–2361 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Prior, S. J. et al. Reduction in midthigh low-density muscle with aerobic exercise training and weight loss impacts glucose tolerance in older men. J. Clin. Endocrinol. Metab. 92, 880–886 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Després, J.-P. & Lemieux, I. Abdominal obesity and metabolic syndrome. Nature 444, 881–887 (2006).

    Article  PubMed  Google Scholar 

  68. Goodpaster, B. H., Kelley, D. E., Wing, R. R., Meier, A. & Thaete, F. L. Effects of weight loss on regional fat distribution and insulin sensitivity in obesity. Diabetes 48, 839–847 (1999).

    Article  CAS  PubMed  Google Scholar 

  69. Goss, A. M. et al. Effects of diet macronutrient composition on body composition and fat distribution during weight maintenance and weight loss. Obesity 21, 1139–1142 (2013).

    Article  PubMed  Google Scholar 

  70. Goss, A. M. et al. Effects of weight loss during a very low carbohydrate diet on specific adipose tissue depots and insulin sensitivity in older adults with obesity: a randomized clinical trial. Nutr. Metab. 17, 64 (2020).

    Article  CAS  Google Scholar 

  71. Mazzali, G. et al. Interrelations between fat distribution, muscle lipid content, adipocytokines, and insulin resistance: effect of moderate weight loss in older women. Am. J. Clin. Nutr. 84, 1193–1199 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Shen, W. et al. Effect of 2-year caloric restriction on organ and tissue size in nonobese 21-to 50-year-old adults in a randomized clinical trial: the CALERIE study. Am. J. Clin. Nutr. 114, 1295–1303 (2021).

    Article  PubMed Central  PubMed  Google Scholar 

  73. Yaskolka Meir, A. et al. Intermuscular adipose tissue and thigh muscle area dynamics during an 18-month randomized weight loss trial. J. Appl. Physiol. 121, 518–527 (2016).

    Article  PubMed  Google Scholar 

  74. Coker, R. H., Williams, R. H., Kortebein, P. M., Sullivan, D. H. & Evans, W. J. Influence of exercise intensity on abdominal fat and adiponectin in elderly adults. Metab. Syndr. Relat. Disord. 7, 363–368 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Cuff, D. J. et al. Effective exercise modality to reduce insulin resistance in women with type 2 diabetes. Diabetes Care 26, 2977–2982 (2003).

    Article  PubMed  Google Scholar 

  76. Goodpaster, B. H. et al. Effects of physical activity on strength and skeletal muscle fat infiltration in older adults: a randomized controlled trial. J. Appl. Physiol. 105, 1498–1503 (2008).

    Article  PubMed Central  PubMed  Google Scholar 

  77. Ikenaga, M. et al. Effects of a 12-week, short-interval, intermittent, low-intensity, slow-jogging program on skeletal muscle, fat infiltration, and fitness in older adults: randomized controlled trial. Eur. J. Appl. Physiol. 117, 7–15 (2017).

    Article  PubMed  Google Scholar 

  78. Jung, J. Y. et al. Effects of aerobic exercise intensity on abdominal and thigh adipose tissue and skeletal muscle attenuation in overweight women with type 2 diabetes mellitus. Diabetes Metab. J. 36, 211–221 (2012).

    Article  PubMed Central  PubMed  Google Scholar 

  79. Ku, Y. et al. Resistance exercise did not alter intramuscular adipose tissue but reduced retinol-binding protein-4 concentration in individuals with type 2 diabetes mellitus. J. Int. Med. Res. 38, 782–791 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Lee, S. et al. Exercise without weight loss is an effective strategy for obesity reduction in obese individuals with and without Type 2 diabetes. J. Appl. Physiol. 99, 1220–1225 (2005).

    Article  PubMed  Google Scholar 

  81. Leskinen, T. et al. Leisure-time physical activity and high-risk fat: a longitudinal population-based twin study. Int. J. Obes. 33, 1211–1218 (2009).

    Article  CAS  Google Scholar 

  82. Manini, T. M. et al. Reduced physical activity increases intermuscular adipose tissue in healthy young adults. Am. J. Clin. Nutr. 85, 377–384 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Poehlman, E. T., Dvorak, R. V., DeNino, W. F., Brochu, M. & Ades, P. A. Effects of resistance training and endurance training on insulin sensitivity in nonobese, young women: a controlled randomized trial. J. Clin. Endocrinol. Metab. 85, 2463–2468 (2000).

    CAS  PubMed  Google Scholar 

  84. Taaffe, D. R. et al. Alterations in muscle attenuation following detraining and retraining in resistance-trained older adults. Gerontology 55, 217–223 (2009).

    Article  PubMed  Google Scholar 

  85. Walts, C. T. et al. Do sex or race differences influence strength training effects on muscle or fat? Med. Sci. Sports Exerc. 40, 669 (2008).

    Article  PubMed Central  PubMed  Google Scholar 

  86. Avila, J. J., Gutierres, J. A., Sheehy, M. E., Lofgren, I. E. & Delmonico, M. J. Effect of moderate intensity resistance training during weight loss on body composition and physical performance in overweight older adults. Eur. J. Appl. Physiol. 109, 517–525 (2010).

    Article  PubMed  Google Scholar 

  87. Brennan, A. M. et al. Weight loss and exercise differentially affect insulin sensitivity, body composition, cardiorespiratory fitness, and muscle strength in older adults with obesity: a randomized controlled trial. J. Gerontol. A 77, 1088–1097 (2022).

    Article  CAS  Google Scholar 

  88. Christiansen, T. et al. Comparable reduction of the visceral adipose tissue depot after a diet-induced weight loss with or without aerobic exercise in obese subjects: a 12-week randomized intervention study. Eur. J. Endocrinol. 160, 759 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Engelson, E. S. et al. Body composition and metabolic effects of a diet and exercise weight loss regimen on obese, HIV-infected women. Metabolism 55, 1327–1336 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Gallagher, D. et al. Changes in adipose tissue depots and metabolic markers following a 1-year diet and exercise intervention in overweight and obese patients with type 2 diabetes. Diabetes Care 37, 3325–3332 (2014).

    Article  PubMed Central  PubMed  Google Scholar 

  91. Janssen, I., Fortier, A., Hudson, R. & Ross, R. Effects of an energy-restrictive diet with or without exercise on abdominal fat, intermuscular fat, and metabolic risk factors in obese women. Diabetes Care 25, 431–438 (2002).

    Article  PubMed  Google Scholar 

  92. Manini, T. M. et al. Effect of dietary restriction and exercise on lower extremity tissue compartments in obese, older women: a pilot study. J. Gerontol. Biol. Sci. Med. Sci. 69, 101–108 (2014).

    Article  Google Scholar 

  93. Murphy, J. C. et al. Preferential reductions in intermuscular and visceral adipose tissue with exercise-induced weight loss compared with calorie restriction. J. Appl. Physiol. 112, 79–85 (2012).

    Article  PubMed  Google Scholar 

  94. Ryan, A. S., Nicklas, B. J., Berman, D. M. & Dennis, K. E. Dietary restriction and walking reduce fat deposition in the midthigh in obese older women. Am. J. Clin. Nutr. 72, 708–713 (2000).

    Article  CAS  PubMed  Google Scholar 

  95. Santanasto, A. J. et al. Impact of weight loss on physical function with changes in strength, muscle mass, and muscle fat infiltration in overweight to moderately obese older adults: a randomized clinical trial. J. Obes. 2011, 516576 (2011).

    Article  PubMed  Google Scholar 

  96. Santanasto, A. J. et al. Effects of changes in regional body composition on physical function in older adults: a pilot randomized controlled trial. J. Nutr. Health Aging 19, 913–921 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  97. Shea, M. K. et al. The effect of pioglitazone and resistance training on body composition in older men and women undergoing hypocaloric weight loss. Obesity 19, 1636–1646 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. Waters, D. L. et al. Effect of aerobic or resistance exercise, or both, on intermuscular and visceral fat and physical and metabolic function in older adults with obesity while dieting. J. Gerontol. A 77, 131–139 (2022).

    Article  Google Scholar 

  99. Toro‐Ramos, T. et al. Continued loss in visceral and intermuscular adipose tissue in weight‐stable women following bariatric surgery. Obesity 23, 62–69 (2015).

    Article  PubMed  Google Scholar 

  100. Miller, G., Carr, J. & Fernandez, A. Regional fat changes following weight reduction from laparoscopic Roux‐en‐Y gastric bypass surgery. Diabetes Obes. Metab. 13, 189–192 (2011).

    Article  CAS  PubMed  Google Scholar 

  101. Taaffe, D. R. et al. The effect of hormone replacement therapy and/or exercise on skeletal muscle attenuation in postmenopausal women: a yearlong intervention. Clin. Physiol. Funct. Imaging 25, 297–304 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Woodhouse, L. J. et al. Dose-dependent effects of testosterone on regional adipose tissue distribution in healthy young men. J. Clin. Endocrinol. Metab. 89, 718–726 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. Goodpaster, B. H. et al. Obesity, regional body fat distribution, and the metabolic syndrome in older men and women. Arch. Intern. Med. 165, 777–783 (2005).

    Article  PubMed  Google Scholar 

  104. Sinha, R. et al. Assessment of skeletal muscle triglyceride content by 1H nuclear magnetic resonance spectroscopy in lean and obese adolescents: relationships to insulin sensitivity, total body fat, and central adiposity. Diabetes 51, 1022–1027 (2002).

    Article  CAS  PubMed  Google Scholar 

  105. Berry, R., Jeffery, E. & Rodeheffer, M. S. Weighing in on adipocyte precursors. Cell Metab. 19, 8–20 (2014).

    Article  CAS  PubMed  Google Scholar 

  106. Crisan, M. et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3, 301–313 (2008).

    Article  CAS  PubMed  Google Scholar 

  107. Lin, G. et al. Defining stem and progenitor cells within adipose tissue. Stem Cell Dev. 17, 1053–1063 (2008).

    Article  CAS  Google Scholar 

  108. Zannettino, A. C. et al. Multipotential human adipose-derived stromal stem cells exhibit a perivascular phenotype in vitro and in vivo. J. Cell Physiol. 214, 413–421 (2008).

    Article  CAS  PubMed  Google Scholar 

  109. Asakura, A., Komaki, M. & Rudnicki, M. Muscle satellite cells are multipotential stem cells that exhibit myogenic, osteogenic, and adipogenic differentiation. Differentiation 68, 245–253 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Wada, M. R., Inagawa-Ogashiwa, M., Shimizu, S., Yasumoto, S. & Hashimoto, N. Generation of different fates from multipotent muscle stem cells. Development 129, 2987–2995 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Gussoni, E. et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401, 390–394 (1999).

    Article  CAS  PubMed  Google Scholar 

  112. Farup, J. et al. Human skeletal muscle CD90+ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients. Cell Metab. 33, 2201–2214 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  113. Natarajan, A., Lemos, D. R. & Rossi, F. M. Fibro/adipogenic progenitors: a double-edged sword in skeletal muscle regeneration. Cell Cycle 9, 2045–2046 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Joe, A. W. et al. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat. Cell Biol. 12, 153–163 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  115. Uezumi, A., Fukada, S.-I., Yamamoto, N., Takeda, S. I. & Tsuchida, K. Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat. Cell Biol. 12, 143–152 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Hafer-Macko, C. E., Yu, S., Ryan, A. S., Ivey, F. M. & Macko, R. F. Elevated tumor necrosis factor-alpha in skeletal muscle after stroke. Stroke 36, 2021–2023 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Kelley, D. E. & Goodpaster, B. H. Stewing in not-so-good juices: interactions of skeletal muscle with adipose secretions. Diabetes 64, 3055–3057 (2015).

    Article  CAS  PubMed  Google Scholar 

  118. Wang, Q. et al. Differentiation of human adipose-derived stem cells into neuron-like cells by Radix Angelicae Sinensis. Neural Regen. Res. 8, 3353–3358 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Zuk, P. A. et al. Human adipose tissue is a source of multipotent stem cells. Mol. Biol. Cell 13, 4279–4295 (2002).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  120. Spalding, K. L. et al. Dynamics of fat cell turnover in humans. Nature 453, 783–787 (2008).

    Article  CAS  PubMed  Google Scholar 

  121. Gil-Ortega, M. et al. Native adipose stromal cells egress from adipose tissue in vivo: evidence during lymph node activation. Stem Cell 31, 1309–1320 (2013).

    Article  CAS  Google Scholar 

  122. Girousse, A. et al. The release of adipose stromal cells from subcutaneous adipose tissue regulates ectopic intramuscular adipocyte deposition. Cell Rep. 27, 323–333 (2019).

    Article  CAS  PubMed  Google Scholar 

  123. Horowitz, M. C. et al. Bone marrow adipocytes. Adipocyte 6, 193–204 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  124. Majka, S. M. et al. De novo generation of white adipocytes from the myeloid lineage via mesenchymal intermediates is age, adipose depot, and gender specific. Proc. Natl Acad. Sci. USA 107, 14781–14786 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  125. Majka, S. M. et al. Adipose lineage specification of bone marrow-derived myeloid cells. Adipocyte 1, 215–229 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  126. Friedenstein, A. J., Chailakhjan, R. K. & Lalykina, K. S. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 3, 393–403 (1970).

    CAS  PubMed  Google Scholar 

  127. Maumus, M., Guerit, D., Toupet, K., Jorgensen, C. & Noel, D. Mesenchymal stem cell-based therapies in regenerative medicine: applications in rheumatology. Stem Cell Res. Ther. 2, 14 (2011).

    Article  PubMed Central  PubMed  Google Scholar 

  128. Rodeheffer, M. S., Birsoy, K. & Friedman, J. M. Identification of white adipocyte progenitor cells in vivo. Cell 135, 240–249 (2008).

    Article  CAS  PubMed  Google Scholar 

  129. Gavin, K. M. et al. De novo generation of adipocytes from circulating progenitor cells in mouse and human adipose tissue. FASEB J. 30, 1096–1108 (2016).

    Article  CAS  PubMed  Google Scholar 

  130. Rydén, M. et al. Transplanted bone marrow-derived cells contribute to human adipogenesis. Cell Metab. 22, 408–417 (2015).

    Article  PubMed  Google Scholar 

  131. Bellows, C. F., Zhang, Y., Chen, J., Frazier, M. L. & Kolonin, M. G. Circulation of progenitor cells in obese and lean colorectal cancer patients. Cancer Epidemiol. Biomark. Prev. 20, 2461–2468 (2011).

    Article  CAS  Google Scholar 

  132. Corvera, S. Cellular heterogeneity in adipose tissues. Annu. Rev. Physiol. 83, 257–278 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  133. Whytock, K. L. et al. Single cell full-length transcriptome of human subcutaneous adipose tissue reveals unique and heterogeneous cell populations. iScience 25, 104772 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  134. Emont, M. P. et al. A single-cell atlas of human and mouse white adipose tissue. Nature 603, 926–933 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  135. Kahn, D. E. & Bergman, B. C. Keeping it local in metabolic disease: adipose tissue paracrine signaling and insulin resistance. Diabetes 71, 599–609 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  136. Lee, H.-J., Park, H.-S., Kim, W., Yoon, D. & Seo, S. Comparison of metabolic network between muscle and intramuscular adipose tissues in Hanwoo beef cattle using a systems biology approach. Int. J. Genom. 2014, 679437 (2014).

    Google Scholar 

  137. Bong, J. J., Cho, K. K. & Baik, M. Comparison of gene expression profiling between bovine subcutaneous and intramuscular adipose tissues by serial analysis of gene expression. Cell Biol. Int. 34, 125–133 (2010).

    CAS  Google Scholar 

  138. Li, M. et al. Co-methylated genes in different adipose depots of pig are associated with metabolic, inflammatory and immune processes. Int. J. Biol. Sci. 8, 831 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  139. Sachs, S. et al. Intermuscular adipose tissue directly modulates skeletal muscle insulin sensitivity in humans. Am. J. Physiol. Endocrinol. Metab. 316, E866–E879 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  140. Lehr, S. et al. Identification and validation of novel adipokines released from primary human adipocytes. Mol. Cell. Proteom. 11, M111.010504 (2012).

    Article  Google Scholar 

  141. Hardin, B. J. et al. TNF-α acts via TNFR1 and muscle-derived oxidants to depress myofibrillar force in murine skeletal muscle. J. Appl. Physiol. 104, 694–699 (2008).

    Article  CAS  PubMed  Google Scholar 

  142. Dietze, D. et al. Impairment of insulin signaling in human skeletal muscle cells by co-culture with human adipocytes. Diabetes 51, 2369–2376 (2002).

    Article  CAS  PubMed  Google Scholar 

  143. Taube, A., Lambernd, S., van Echten-Deckert, G., Eckardt, K. & Eckel, J. Adipokines promote lipotoxicity in human skeletal muscle cells. Arch. Physiol. Biochem. 118, 92–101 (2012).

    Article  CAS  PubMed  Google Scholar 

  144. Lam, Y. Y. et al. The use of adipose tissue-conditioned media to demonstrate the differential effects of fat depots on insulin-stimulated glucose uptake in a skeletal muscle cell line. Obes. Res. Clin. Pract. 5, e43–e54 (2011).

    Article  Google Scholar 

  145. Pellegrinelli, V. et al. Human adipocytes induce inflammation and atrophy in muscle cells during obesity. Diabetes 64, 3121–3134 (2015).

    Article  CAS  PubMed  Google Scholar 

  146. Laurens, C. et al. Adipogenic progenitors from obese human skeletal muscle give rise to functional white adipocytes that contribute to insulin resistance. Int. J. Obes. 40, 497–506 (2016).

    Article  CAS  Google Scholar 

  147. Lyu, K. et al. Short-term overnutrition induces white adipose tissue insulin resistance through sn-1, 2-diacylglycerol/PKCε/insulin receptor Thr1160 phosphorylation. J. Clin. Invest. Insight 6, e139946 (2021).

    Google Scholar 

  148. Bergman, B., Hunerdosse, D., Kerege, A., Playdon, M. & Perreault, L. Localisation and composition of skeletal muscle diacylglycerol predicts insulin resistance in humans. Diabetologia 55, 1140–1150 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  149. Perreault, L. et al. Intracellular localization of diacylglycerols and sphingolipids influences insulin sensitivity and mitochondrial function in human skeletal muscle. J. Clin. Invest. Insight 3, e96805 (2018).

    Google Scholar 

  150. Chan, P. C., Hsiao, F. C., Chang, H. M., Wabitsch, M. & Hsieh, P. S. Importance of adipocyte cyclooxygenase‐2 and prostaglandin E2‐prostaglandin E receptor 3 signaling in the development of obesity‐induced adipose tissue inflammation and insulin resistance. FASEB J. 30, 2282–2297 (2016).

    Article  CAS  PubMed  Google Scholar 

  151. Nunemaker, C. S. et al. 12-Lipoxygenase-knockout mice are resistant to inflammatory effects of obesity induced by Western diet. Am. J. Physiol. Endocrinol. Metab. 295, E1065–E1075 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  152. Powell, W. S. & Rokach, J. Biochemistry, biology and chemistry of the 5-lipoxygenase product 5-oxo-ETE. Prog. Lipid Res. 44, 154–183 (2005).

    Article  CAS  PubMed  Google Scholar 

  153. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).

    Article  CAS  PubMed  Google Scholar 

  154. Hotta, K. et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler. Thromb. Vasc. Biol. 20, 1595–1599 (2000).

    Article  CAS  PubMed  Google Scholar 

  155. Fain, J. N., Madan, A. K., Hiler, M. L., Cheema, P. & Bahouth, S. W. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology 145, 2273–2282 (2004).

    Article  CAS  PubMed  Google Scholar 

  156. Miljkovic, I. et al. Greater skeletal muscle fat infiltration is associated with higher all-cause and cardiovascular mortality in older men. J. Gerontol. A Biom. Sci. Med. Sci. 70, 1133–1140 (2015).

    Article  CAS  Google Scholar 

  157. Miljkovic, I. et al. Skeletal muscle adiposity is associated with serum lipid and lipoprotein levels in Afro‐Caribbean men. Obesity 21, 1900–1907 (2013).

    Article  CAS  PubMed  Google Scholar 

  158. Kahn, D. et al. Quantifying the inflammatory secretome of human intermuscular adipose tissue. Physiol. Rep. 10, e15424 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge the contributions of David E. Kelley, M.D. (retired associate vice president cardiometabolic disease, Merck Research Laboratories, Rahway, NJ, USA), Anne B. Newman, M.D. (School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA) and Tamara B. Harris, M.D. (retired, National Institute on Aging, Bethesda, MD, USA) to the study of IMAT.

Author information

Authors and Affiliations

  1. Translational Research Institute, AdventHealth, Orlando, FL, USA

    Bret H. Goodpaster, Andrea M. Brennan & Lauren M. Sparks

  2. Division of Endocrinology, Diabetes, and Metabolism, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Bryan C. Bergman

Authors
  1. Bret H. Goodpaster
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bryan C. Bergman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrea M. Brennan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lauren M. Sparks
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Bret H. Goodpaster.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Endocrinology thanks Ellen Blaak, Matthijs Hesselink and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Goodpaster, B.H., Bergman, B.C., Brennan, A.M. et al. Intermuscular adipose tissue in metabolic disease. Nat Rev Endocrinol 19, 285–298 (2023). https://doi.org/10.1038/s41574-022-00784-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-022-00784-2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing