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1. 1
   Number 1: Is Obesity A Muscle Problem?

   Muscle is where most of the glucose goes, and muscle insulin resistance is the first thing that breaks on the road to type 2 diabetes. Both of those are true, and neither one means that building more muscle is the treatment for obesity. This episode works through what actually decides whether a tissue handles fuel well: not how much of it you have, but how fast it's moving fuel through. We go through the one-legged exercise studies, the 18,000-person analysis of what body composition actually predicts, the athlete's paradox, the energy cost of building a kilogram of muscle, the GLP-1 lean mass panic, and why sarcopenic obesity is named after the wrong organ. This is part two of a two-part series on storage capacity. Part one covered where body fat goes and what happens when the storage runs out. Timestamps0:00 The one-leg study, and the muscle-centric claim02:06 What obesity is, and the garage analogy05:06 How glucose gets into a muscle cell11:21 Insulin sensitivity improves without building muscle17:11 The best case for muscle-centric medicine21:13 What predicts falls and death: strength, not lean mass25:18 Separating muscle size from muscle function31:33 Liver fat: amount, type, and flux37:54 Should you build muscle first? The arithmetic42:37 Building muscle in a calorie deficit50:29 GLP-1s, DXA, and the lean mass panic58:23 Sarcopenic obesity, and why the name is wrong01:04:37 Why size still tells you something01:11:46 So what is obesity? Resources: Buy the book, Signal: https://www.barbellmedicine.com/shop/learning/signal/ New Barbell Medicine Hybrid 5K and 10K Run + Lift Programs Barbell Medicine coaching and templates: https://www.barbellmedicine.com 1. Richter EA, Mikines KJ, Galbo H, Kiens B. Effect of exercise on insulin action in human skeletal muscle. J Appl Physiol (1985). 1989;66(2):876-885. doi:10.1152/jappl.1989.66.2.876. PMID: 2496078. https://doi.org/10.1152/jappl.1989.66.2.876 2. Cawthon PM, Travison TG, Manini TM, et al. Establishing the link between lean mass and grip strength cut points with mobility disability and other health outcomes. J Gerontol A Biol Sci Med Sci. 2020;75(7):1317-1323. doi:10.1093/gerona/glz081. PMID: 30869772. https://doi.org/10.1093/gerona/glz081 3. Bhasin S, Travison TG, Manini TM, et al. Sarcopenia definition: the position statements of the Sarcopenia Definition and Outcomes Consortium. J Am Geriatr Soc. 2020;68(7):1410-1418. doi:10.1111/jgs.16372. PMID: 32150289. https://doi.org/10.1111/jgs.16372 4. Elgaddal N, Kramarow EA, Reuben C. Physical activity among adults aged 18 and over: United States, 2020. NCHS Data Brief No. 443. Hyattsville, MD: National Center for Health Statistics; 2022. PMID: 36043905. https://www.cdc.gov/nchs/products/databriefs/db443.htm 5. Whitfield GP, Carlson SA, Ussery EN, Fulton JE, Galuska DA, Petersen R. Trends in meeting physical activity guidelines among urban and rural dwelling adults, United States, 2008-2017. MMWR Morb Mortal Wkly Rep. 2019;68(23):513-518. doi:10.15585/mmwr.mm6823a1. PMID: 31194722. https://doi.org/10.15585/mmwr.mm6823a1 6. Wang T, Wang J, Hu X, Huang XJ, Chen GX. Current understanding of glucose transporter 4 expression and functional mechanisms. World J Biol Chem. 2020;11(3):76-98. doi:10.4331/wjbc.v11.i3.76. PMID: 33274014. https://doi.org/10.4331/wjbc.v11.i3.76 7. DeFronzo RA, Tripathy D. Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care. 2009;32(Suppl 2):S157-S163. doi:10.2337/dc09-S302. PMID: 19875544. https://doi.org/10.2337/dc09-S302 8. Richter EA, Hargreaves M. Exercise, GLUT4, and skeletal muscle glucose uptake. Physiol Rev. 2013;93(3):993-1017. doi:10.1152/physrev.00038.2012. PMID: 23899560. https://doi.org/10.1152/physrev.00038.2012 9. Petersen KF, Dufour S, Savage DB, et al. The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc Natl Acad Sci U S A. 2007;104(31):12587-12594. doi:10.1073/pnas.0705408104. PMID: 17640906. https://doi.org/10.1073/pnas.0705408104 10. Rabøl R, Petersen KF, Dufour S, Flannery C, Shulman GI. Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals. Proc Natl Acad Sci U S A. 2011;108(33):13705-13709. doi:10.1073/pnas.1110105108. PMID: 21808028. https://doi.org/10.1073/pnas.1110105108 11. Perseghin G, Price TB, Petersen KF, et al. Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects. N Engl J Med. 1996;335(18):1357-1362. doi:10.1056/NEJM199610313351804. PMID: 8857019. https://doi.org/10.1056/NEJM199610313351804 12. Mikines KJ, Sonne B, Farrell PA, Tronier B, Galbo H. Effect of physical exercise on sensitivity and responsiveness to insulin in humans. Am J Physiol. 1988;254(3 Pt 1):E248-E259. doi:10.1152/ajpendo.1988.254.3.E248. PMID: 3126668. https://doi.org/10.1152/ajpendo.1988.254.3.E248 13. Mikines KJ, Sonne B, Tronier B, Galbo H. Effects of acute exercise and detraining on insulin action in trained men. J Appl Physiol (1985). 1989;66(2):704-711. doi:10.1152/jappl.1989.66.2.704. PMID: 2496077. https://doi.org/10.1152/jappl.1989.66.2.704 14. Yu R, Duncombe SL, Nemoto Y, et al. Physical activity trajectories and mortality. Br J Sports Med. 2025;59(17):1228-1241. doi:10.1136/bjsports-2024-109122. PMID: 40639966. https://doi.org/10.1136/bjsports-2024-109122 15. Saint-Maurice PF, Coughlan D, Kelly SP, et al. Association of leisure-time physical activity across the adult life course with all-cause and cause-specific mortality. JAMA Netw Open. 2019;2(3):e190355. doi:10.1001/jamanetworkopen.2019.0355. PMID: 30848809. https://doi.org/10.1001/jamanetworkopen.2019.0355 16. Wang Y, Luo D, Liu J, Song Y, Jiang B, Jiang H. Low skeletal muscle mass index and all-cause mortality. PLoS One. 2023;18(6):e0286745. doi:10.1371/journal.pone.0286745. PMID: 37288745. https://doi.org/10.1371/journal.pone.0286745 17. Umpierre D, Ribeiro PAB, Kramer CK, et al. Physical activity advice only or structured exercise training and association with HbA1c levels in type 2 diabetes. JAMA. 2011;305(17):1790-1799. doi:10.1001/jama.2011.576. PMID: 21540423. https://doi.org/10.1001/jama.2011.576 18. Goodpaster BH, Carlson CL, Visser M, et al. Attenuation of skeletal muscle and strength in the elderly: the Health ABC Study. J Appl Physiol (1985). 2001;90(6):2157-2165. doi:10.1152/jappl.2001.90.6.2157. PMID: 11356778. https://doi.org/10.1152/jappl.2001.90.6.2157 19. Paquin J, Lagacé JC, Brochu M, Dionne IJ. Exercising for insulin sensitivity, is there a mechanistic relationship with quantitative changes in skeletal muscle mass? Front Physiol. 2021;12:656909. doi:10.3389/fphys.2021.656909. PMID: 34054574. https://doi.org/10.3389/fphys.2021.656909 20. Eriksson J, Taimela S, Eriksson K, Parviainen S, Peltonen J, Kujala U. Resistance training in the treatment of non-insulin-dependent diabetes mellitus. Int J Sports Med. 1997;18(4):242-246. doi:10.1055/s-2007-972627. PMID: 9231838. https://doi.org/10.1055/s-2007-972627 21. Cuff DJ, Meneilly GS, Martin A, Ignaszewski A, Tildesley HD, Frohlich JJ. Effective exercise modality to reduce insulin resistance in women with type 2 diabetes. Diabetes Care. 2003;26(11):2977-2982. doi:10.2337/diacare.26.11.2977. PMID: 14578226. https://doi.org/10.2337/diacare.26.11.2977 22. Bucci M, Huovinen V, Guzzardi MA, et al. Resistance training improves skeletal muscle insulin sensitivity in elderly offspring of overweight and obese mothers. Diabetologia. 2016;59(1):77-86. doi:10.1007/s00125-015-3780-8. PMID: 26486356. https://doi.org/10.1007/s00125-015-3780-8 23. Mavros Y, Kay S, Anderberg KA, et al. Changes in insulin resistance and HbA1c are related to exercise-mediated changes in body composition in older adults with type 2 diabetes: interim outcomes from the GREAT2DO trial. Diabetes Care. 2013;36(8):2372-2379. doi:10.2337/dc12-2196. PMID: 23474589. https://doi.org/10.2337/dc12-2196 24. Janssen I, Heymsfield SB, Wang ZM, Ross R. Skeletal muscle mass and distribution in 468 men and women aged 18-88 yr. J Appl Physiol (1985). 2000;89(1):81-88. doi:10.1152/jappl.2000.89.1.81. PMID: 10904038. https://doi.org/10.1152/jappl.2000.89.1.81 25. Orwoll ES, Peters KE, Hellerstein M, Cummings SR, Evans WJ, Cawthon PM. The importance of muscle versus fat mass in sarcopenic obesity: a re-evaluation using D3-creatine muscle mass versus DXA lean mass measurements. J Gerontol A Biol Sci Med Sci. 2020;75(7):1362-1368. doi:10.1093/gerona/glaa064. PMID: 32232396. https://doi.org/10.1093/gerona/glaa064 26. Holten MK, Zacho M, Gaster M, Juel C, Wojtaszewski JFP, Dela F. Strength training increases insulin-mediated glucose uptake, GLUT4 content, and insulin signaling in skeletal muscle in patients with type 2 diabetes. Diabetes. 2004;53(2):294-305. doi:10.2337/diabetes.53.2.294. PMID: 14747278. https://doi.org/10.2337/diabetes.53.2.294 27. Manca A, Dragone D, Dvir Z, Deriu F. Cross-education of muscular strength following unilateral resistance training: a meta-analysis. Eur J Appl Physiol. 2017;117(11):2335-2354. doi:10.1007/s00421-017-3720-z. PMID: 28936703. https://doi.org/10.1007/s00421-017-3720-z 28. Bilet L, Phielix E, van de Weijer T, et al. One-leg inactivity induces a reduction in mitochondrial oxidative capacity, intramyocellular lipid accumulation and reduced insulin signalling upon lipid infusion. Diabetologia. 2020;63(6):1211-1222. doi:10.1007/s00125-020-05128-1. PMID: 32185462. https://doi.org/10.1007/s00125-020-05128-1 29. Lee J, Kim D, Kim C. Resistance training for glycemic control, muscular strength, and lean body mass in old type 2 diabetic patients: a meta-analysis. Diabetes Ther. 2017;8(3):459-473. doi:10.1007/s13300-017-0258-3. PMID: 28382531. https://doi.org/10.1007/s13300-017-0258-3 30. Goodpaster BH, He J, Watkins S, Kelley DE. Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab. 2001;86(12):5755-5761. doi:10.1210/jcem.86.12.8075. PMID: 11739435. https://doi.org/10.1210/jcem.86.12.8075 31. Amati F, Dubé JJ, Alvarez-Carnero E, et al. Skeletal muscle triglycerides, diacylglycerols, and ceramides in insulin resistance: another paradox in endurance-trained athletes? Diabetes. 2011;60(10):2588-2597. doi:10.2337/db10-1221. PMID: 21873552. https://doi.org/10.2337/db10-1221 32. Bergman BC, Perreault L, Hunerdosse DM, Koehler MC, Samek AM, Eckel RH. Increased intramuscular lipid synthesis and low saturation relate to insulin sensitivity in endurance-trained athletes. J Appl Physiol (1985). 2010;108(5):1134-1141. doi:10.1152/japplphysiol.00684.2009. PMID: 20299618. https://doi.org/10.1152/japplphysiol.00684.2009 33. Dubé JJ, Amati F, Stefanovic-Racic M, Toledo FGS, Sauers SE, Goodpaster BH. Exercise-induced alterations in intramyocellular lipids and insulin resistance: the athlete's paradox revisited. Am J Physiol Endocrinol Metab. 2008;294(5):E882-E888. doi:10.1152/ajpendo.00769.2007. PMID: 18319352. https://doi.org/10.1152/ajpendo.00769.2007 34. Dubé JJ, Amati F, Toledo FGS, et al. Effects of weight loss and exercise on insulin resistance, and intramyocellular triacylglycerol, diacylglycerol and ceramide. Diabetologia. 2011;54(5):1147-1156. doi:10.1007/s00125-011-2065-0. PMID: 21327867. https://doi.org/10.1007/s00125-011-2065-0 35. Ter Horst KW, Vatner DF, Zhang D, et al. Hepatic insulin resistance is not pathway selective in humans with nonalcoholic fatty liver disease. Cell Rep. 2017;19(10):1997-2004. doi:10.1016/j.celrep.2017.05.035. PMID: 28591572. PMCID: PMC5469939. https://doi.org/10.1016/j.celrep.2017.05.035 36. Lyu K, Zhang Y, Zhang D, et al. A membrane-bound diacylglycerol species induces PKCepsilon-mediated hepatic insulin resistance. Cell Metab. 2020;32(4):654-664.e5. doi:10.1016/j.cmet.2020.08.001. PMID: 32882164. PMCID: PMC7544641. https://doi.org/10.1016/j.cmet.2020.08.001 37. Sargeant JA, Gray LJ, Bodicoat DH, et al. The effect of exercise training on intrahepatic triglyceride and hepatic insulin sensitivity: a systematic review and meta-analysis. Obes Rev. 2018;19(10):1446-1459. doi:10.1111/obr.12719. PMID: 30092609. https://doi.org/10.1111/obr.12719 38. Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78(6):1966-1986. doi:10.1097/HEP.0000000000000520. PMID: 37363821. https://doi.org/10.1097/HEP.0000000000000520 39. Stine JG, DiJoseph K, Pattison Z, et al. Exercise training is associated with treatment response in liver fat content by magnetic resonance imaging independent of clinically significant body weight loss in patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis. Am J Gastroenterol. 2023;118(7):1204-1213. doi:10.14309/ajg.0000000000002098. PMID: 36705333. https://doi.org/10.14309/ajg.0000000000002098 40. Mucinski JM, Salvador AF, Moore MP, et al. Histological improvements following energy restriction and exercise: the role of insulin resistance in resolution of MASH. J Hepatol. 2024;81(5):781-793. doi:10.1016/j.jhep.2024.06.017. PMID: 38914313. PMCID: PMC12007730. ClinicalTrials.gov NCT03151798. https://doi.org/10.1016/j.jhep.2024.06.017 41. Nikolaidis MG, Paschalis V, Margaritelis NV. The energetic cost of building human skeletal muscle. bioRxiv. Preprint posted August 20, 2026. doi:10.64898/2026.08.17.745156. Preprint, not peer reviewed. https://doi.org/10.64898/2026.08.17.745156 42. Helms ER, Spence AJ, Sousa C, et al. Effect of small and large energy surpluses on strength, muscle, and skinfold thickness in resistance-trained individuals: a parallel groups design. Sports Med Open. 2023;9(1):102. doi:10.1186/s40798-023-00651-y. PMID: 37914977. https://doi.org/10.1186/s40798-023-00651-y 43. Murphy C, Koehler K. Energy deficiency impairs resistance training gains in lean mass but not strength: a meta-analysis and meta-regression. Scand J Med Sci Sports. 2022;32(1):125-137. doi:10.1111/sms.14075. PMID: 34623696. https://doi.org/10.1111/sms.14075 44. Elia M, Stubbs RJ, Henry CJ. Differences in fat, carbohydrate, and protein metabolism between lean and obese subjects undergoing total starvation. Obes Res. 1999;7(6):597-604. doi:10.1002/j.1550-8528.1999.tb00720.x. PMID: 10574520. https://doi.org/10.1002/j.1550-8528.1999.tb00720.x 45. Colles SL, Dixon JB, Marks P, Strauss BJ, O'Brien PE. Preoperative weight loss with a very-low-energy diet: quantitation of changes in liver and abdominal fat by serial imaging. Am J Clin Nutr. 2006;84(2):304-311. doi:10.1093/ajcn/84.1.304. PMID: 16895876. https://doi.org/10.1093/ajcn/84.1.304 46. Vargas-Molina S, García-Palumbo A, García-Sillero M, et al. Effects of a moderate caloric deficit on body composition in resistance-trained individuals. Eur J Appl Physiol. 2026;126(7):4019-4030. doi:10.1007/s00421-026-06209-6. PMID: 41940947. https://doi.org/10.1007/s00421-026-06209-6 47. Longland TM, Oikawa SY, Mitchell CJ, Devries MC, Phillips SM. Higher compared with lower dietary protein during an energy deficit combined with intense exercise promotes greater lean mass gain and fat mass loss: a randomized trial. Am J Clin Nutr. 2016;103(3):738-746. doi:10.3945/ajcn.115.119339. PMID: 26817506. https://doi.org/10.3945/ajcn.115.119339 48. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183. PMID: 33567185. https://doi.org/10.1056/NEJMoa2032183 49. Wilding JPH, Batterham RL, Davies M, et al. Impact of semaglutide on body composition in adults with overweight or obesity: exploratory analysis of the STEP 1 study. J Endocr Soc. 2021;5(Suppl 1):A16-A17. doi:10.1210/jendso/bvab048.030. https://doi.org/10.1210/jendso/bvab048.030 50. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216. doi:10.1056/NEJMoa2206038. PMID: 35658024. https://doi.org/10.1056/NEJMoa2206038 51. Look M, Dunn JP, Kushner RF, et al. Body composition changes during weight reduction with tirzepatide in the SURMOUNT-1 study of adults with obesity or overweight. Diabetes Obes Metab. 2025;27(5):2720-2729. doi:10.1111/dom.16275. PMID: 39996356. https://doi.org/10.1111/dom.16275 52. Wang Z, Deurenberg P, Wang W, Pietrobelli A, Baumgartner RN, Heymsfield SB. Hydration of fat-free body mass: review and critique of a classic body-composition constant. Am J Clin Nutr. 1999;69(5):833-841. doi:10.1093/ajcn/69.5.833. PMID: 10232621. https://doi.org/10.1093/ajcn/69.5.833 53. Wang ZM, Pierson RN Jr, Heymsfield SB. The five-level model: a new approach to organizing body-composition research. Am J Clin Nutr. 1992;56(1):19-28. doi:10.1093/ajcn/56.1.19. PMID: 1609756. https://doi.org/10.1093/ajcn/56.1.19 54. Wadden TA, Neiberg RH, Wing RR, et al. Four-year weight losses in the Look AHEAD study: factors associated with long-term success. Obesity (Silver Spring). 2011;19(10):1987-1998. doi:10.1038/oby.2011.230. PMID: 21779086. https://doi.org/10.1038/oby.2011.230 55. Fildes A, Charlton J, Rudisill C, Littlejohns P, Prevost AT, Gulliford MC. Probability of an obese person attaining normal body weight: cohort study using electronic health records. Am J Public Health. 2015;105(9):e54-e59. doi:10.2105/AJPH.2015.302773. PMID: 26180980. https://doi.org/10.2105/AJPH.2015.302773 56. Alissou M, Demangeat T, Folope V, et al. Effect of semaglutide on sarcopenic obesity. Diabetes Obes Metab. 2026;28(1):112-121. doi:10.1111/dom.70141. PMID: 41068996. https://doi.org/10.1111/dom.70141 57. Bansal MB, Patton H, Morgan TR, Carr RM, Dranoff JA, Allen AM. Semaglutide therapy for metabolic dysfunction-associated steatohepatitis: November 2025 updates to AASLD Practice Guidance. Hepatology. 2025;83(5):1326-1340. doi:10.1097/HEP.0000000000001608. PMID: 41201884. https://doi.org/10.1097/HEP.0000000000001608 58. Sardeli AV, Komatsu TR, Mori MA, Gáspari AF, Chacon-Mikahil MPT. Resistance training prevents muscle loss induced by caloric restriction in obese elderly individuals: a systematic review and meta-analysis. Nutrients. 2018;10(4):423. doi:10.3390/nu10040423. PMID: 29596307. https://doi.org/10.3390/nu10040423 59. Rosenberg IH. Summary comments. Am J Clin Nutr. 1989;50(5):1231-1233. doi:10.1093/ajcn/50.5.1231. Not indexed in PubMed. https://doi.org/10.1093/ajcn/50.5.1231 60. Rosenberg IH. Sarcopenia: origins and clinical relevance. J Nutr. 1997;127(5 Suppl):990S-991S. doi:10.1093/jn/127.5.990S. PMID: 9164280. https://doi.org/10.1093/jn/127.5.990S 61. Kirk B, Cawthon PM, Arai H, et al. The conceptual definition of sarcopenia: Delphi consensus from the Global Leadership Initiative in Sarcopenia. Age Ageing. 2024;53(3):afae052. doi:10.1093/ageing/afae052. PMID: 38520141. https://doi.org/10.1093/ageing/afae052 62. Goodpaster BH, Park SW, Harris TB, et al. The loss of skeletal muscle strength, mass, and quality in older adults: the Health, Aging and Body Composition Study. J Gerontol A Biol Sci Med Sci. 2006;61(10):1059-1064. doi:10.1093/gerona/61.10.1059. PMID: 17077199. https://doi.org/10.1093/gerona/61.10.1059 63. Pascual-Fernández J, Fernández-Montero A, Córdova-Martínez A, Pastor D, Martínez-Rodríguez A, Roche E. Sarcopenia: molecular pathways and potential targets for intervention. Int J Mol Sci. 2020;21(22):8844. doi:10.3390/ijms21228844. PMID: 33266508. https://doi.org/10.3390/ijms21228844 64. Kwon YN, Yoon SS. Sarcopenia: neurological point of view. J Bone Metab. 2017;24(2):83-89. doi:10.11005/jbm.2017.24.2.83. PMID: 28642851. https://doi.org/10.11005/jbm.2017.24.2.83 65. Batsis JA, Villareal DT. Sarcopenic obesity in older adults: aetiology, epidemiology and treatment strategies. Nat Rev Endocrinol. 2018;14(9):513-537. doi:10.1038/s41574-018-0062-9. PMID: 30065268. https://doi.org/10.1038/s41574-018-0062-9 66. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563. PMID: 37952131. https://doi.org/10.1056/NEJMoa2307563 67. Deanfield J, Lincoff AM, Kahn SE, et al. Impact of semaglutide on cardiovascular outcomes by adiposity measures in SELECT. Lancet. 2025;406(10516):2257-2268. doi:10.1016/S0140-6736(25)01375-3. PMID: 41138739. https://doi.org/10.1016/S0140-6736(25)01375-3 68. Perkovic V, Tuttle KR, Rossing P, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med. 2024;391(2):109-121. doi:10.1056/NEJMoa2403347. PMID: 38785209. https://doi.org/10.1056/NEJMoa2403347 69. Obesity Medicine Association. Definition of obesity. https://obesitymedicine.org/blog/why-is-obesity-a-disease/ 70. Tomiyama AJ, Hunger JM, Nguyen-Cuu J, Wells C. Misclassification of cardiometabolic health when using body mass index categories in NHANES 2005-2012. Int J Obes (Lond). 2016;40(5):883-886. doi:10.1038/ijo.2016.17. PMID: 26841729. https://doi.org/10.1038/ijo.2016.17 Advertising Inquiries: https://redcircle.com/brands

   September 04, 2026·1h 18min
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2. 2
   Number 2: Who Needs Testosterone, and Who's Not Getting It I Signal Episode 4

   Most men who start testosterone never needed it, and some who genuinely do never get treated. In the final episode of the Signal series, Dr. Jordan Feigenbaum and Dr. Austin Baraki work through who actually needs testosterone replacement, who got sold it, and what the evidence says about the risks that scared the field for a decade. We cover the blinded trial where men couldn't tell real testosterone from placebo, what the heart and prostate data actually show now that we have the trials, what testosterone does to fertility, and the framework we use to decide. We also close the story of Mark, the patient whose lab result started the series. This is educational content, not medical advice. Talk to your physician about your personal situation. Here we cover the real diagnosis of testosterone deficiency, primary versus secondary low testosterone, how the system both over- and under-prescribes, the SHBG trap that makes a normal level look low, the gray-zone crossover study, what replacement should actually target, why most men quit within a year, testosterone as a male contraceptive, the TRAVERSE cardiovascular results, the saturation model and prostate safety, the blood side effect worth monitoring, and when not to start at all. Timestamps: 00:00 The study almost nobody mentions 01:31 Who this episode is for 03:35 What a real testosterone diagnosis requires 07:18 Primary vs secondary low testosterone 10:12 How testosterone gets over-prescribed 11:35 The SHBG trap: when a low number misleads 18:10 Would GLP-1 plus testosterone work better? 22:19 Why genuine deficiency gets under-treated 24:15 The cardiovascular scare and where it came from 34:11 The gray-zone study, in full 41:02 What TRT should actually target, and the "900" myth 47:38 Running TRT as a trial, and why 70% quit 52:36 Testosterone as a contraceptive: the fertility cost 57:19 Does TRT cause heart problems? The TRAVERSE trial 01:01:40 Testosterone and the prostate 01:09:13 The blood side effect worth watching 01:12:02 When not to start testosterone 01:14:26 Who actually benefits from TRT 01:18:28 The Signal framework, and what happened to Mark 01:21:14 Five things to take away 01:23:33 Our conflict of interest, and the book Resources: Buy the book, Signal: https://www.barbellmedicine.com/shop/learning/signal/Part 1: Is the testosterone crisis real?Part 2: Is you testosterone actually low?Part 3: What's actually driving your testosterone down? New Barbell Medicine Hybrid 5K and 10K Run + Lift Programs Barbell Medicine coaching and templates: https://www.barbellmedicine.com Testosterone Action Plan: https://www.barbellmedicine.com/testosterone-action-plan/ Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60(7):762-769. doi:10.1111/j.1742-1241.2006.00992.xBaillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001-2011. JAMA Intern Med. 2013;173(15):1465-1466. doi:10.1001/jamainternmed.2013.6895Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744. doi:10.1210/jc.2018-00229Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and management of testosterone deficiency: AUA guideline. J Urol. 2018;200(2):423-432. doi:10.1016/j.juro.2018.03.115Corona G, Goulis DG, Huhtaniemi I, et al. European Academy of Andrology (EAA) and European Society of Endocrinology (ESE) recommendations on the diagnosis and management of male hypogonadism. Andrology. 2020;8(5):970-987. doi:10.1111/andr.12770Morgentaler A, Zitzmann M, Traish AM, et al. Commentary: who is a candidate for testosterone therapy? A synthesis of international expert opinions. J Sex Med. 2014;11(7):1636-1645. doi:10.1111/jsm.12546Mok SF, Fennell C, Savkovic S, et al. Testosterone for androgen deficiency-like symptoms in men without pathologic hypogonadism: a randomized, placebo-controlled cross-over with masked choice extension clinical trial. J Gerontol A Biol Sci Med Sci. 2020;75(9):1723-1731. doi:10.1093/gerona/glz195Clift AK, Johnson H, Huang DR, Morgentaler A. Real-world outcomes and safety of testosterone therapy: a longitudinal, retrospective cohort study of over 9,000 men. World J Mens Health. 2026;44(2):438-450. doi:10.5534/wjmh.250245Malik RD, Wang CE, Lapin B, Lakeman JC, Helfand BT. Characteristics of men undergoing testosterone replacement therapy and adherence to follow-up recommendations in a metropolitan multicenter health care system. Urology. 2015;85(6):1382-1388. doi:10.1016/j.urology.2015.01.027Donatucci C, Cui Z, Fang Y, Muram D. Long-term treatment patterns of testosterone replacement medications. J Sex Med. 2014;11(8):2092-2099. doi:10.1111/jsm.12608Saad F, Aversa A, Isidori AM, Zafalon L, Zitzmann M, Gooren L. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol. 2011;165(5):675-685. doi:10.1530/EJE-11-0221Ly LP, Liu PY, Handelsman DJ. Rates of suppression and recovery of human sperm output in testosterone-based hormonal contraceptive regimens. Hum Reprod. 2005;20(6):1733-1740. doi:10.1093/humrep/deh834Liu PY, Swerdloff RS, Christenson PD, Handelsman DJ, Wang C; Hormonal Male Contraception Summit Group. Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis. Lancet. 2006;367(9520):1412-1420. doi:10.1016/S0140-6736(06)68614-5Ko EY, Siddiqi K, Brannigan RE, Sabanegh ES Jr. Empirical medical therapy for idiopathic male infertility: a survey of the American Urological Association. J Urol. 2012;187(3):973-978. doi:10.1016/j.juro.2011.10.137Kohn TP, Louis MR, Pickett SM, et al. Age and duration of testosterone therapy predict time to return of sperm count after human chorionic gonadotropin therapy. Fertil Steril. 2017;107(2):351-357.e1. doi:10.1016/j.fertnstert.2016.10.004Wenker EP, Dupree JM, Langille GM, et al. The use of HCG-based combination therapy for recovery of spermatogenesis after testosterone use. J Sex Med. 2015;12(6):1334-1337. doi:10.1111/jsm.12890Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363(2):109-122. doi:10.1056/NEJMoa1000485Vigen R, O’Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829-1836. doi:10.1001/jama.2013.280386Basaria S, Harman SM, Travison TG, et al. Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial. JAMA. 2015;314(6):570-581. doi:10.1001/jama.2015.8881Budoff MJ, Ellenberg SS, Lewis CE, et al. Testosterone treatment and coronary artery plaque volume in older men with low testosterone. JAMA. 2017;317(7):708-716. doi:10.1001/jama.2016.21043Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular safety of testosterone-replacement therapy. N Engl J Med. 2023;389(2):107-117. doi:10.1056/NEJMoa2215025Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1(4):293-297.Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol. 2009;55(2):310-320. doi:10.1016/j.eururo.2008.09.024Khera M, Crawford D, Morales A, Salonia A, Morgentaler A. A new era of testosterone and prostate cancer: from physiology to clinical implications. Eur Urol. 2014;65(1):115-123. doi:10.1016/j.eururo.2013.08.015Bhasin S, Lincoff AM, Nissen SE, et al. Prostate safety events during testosterone replacement therapy in men with hypogonadism: a randomized clinical trial. JAMA Netw Open. 2023;6(12):e2348692. doi:10.1001/jamanetworkopen.2023.48692Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment in older men. N Engl J Med. 2016;374(7):611-624. doi:10.1056/NEJMoa1506119 Advertising Inquiries: https://redcircle.com/brands

   August 27, 2026·1h 27min
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3. 3
   Number 3: The Protein Scaries: What the Research Says About Your Kidneys, Cancer, Bones, and Body Fat

   Every couple of years a new headline warns that the protein you eat is quietly hurting you. This year the target is your kidneys. Before that it was cancer, then your bones, then the claim that your body can only use twenty or thirty grams of protein at a meal. In this episode, Dr. Jordan Feigenbaum goes through the actual studies behind each scare: the kidney trials, the 2014 IGF-1 and cancer paper that started the panic, the acid-ash bone hypothesis, and the per-meal "cap." Each fear starts from a real mechanism, and each one was run straight to a frightening conclusion the clinical outcomes never supported. The take home is simple. For a healthy adult, protein is not the lever people think it is, and where a real signal exists (processed and red meat, or a kidney that is already diseased) it tracks the whole dietary pattern more than the protein number. The two things that actually decide your health here are whether you eat mostly real food and whether you train. Timestamps00:00 The protein scare cycle 01:23 The four fears 01:59 Kidneys: healthy kidneys under higher protein 06:22 Kidney disease: does cutting protein help? 09:38 Red meat and the dietary pattern, not protein 12:00 Muscle, aging, and lifting on a restricted diet 13:54 Cancer: IGF-1 and the 2014 study everyone cites 16:22 The age reversal, and what travels with protein 18:48 Bigger data, processed meat, and the IGF-1 tell 22:15 Bones and the acid-ash myth 25:13 The 30-gram cap 27:17 What protein actually does, and how much you need 32:20 The two questions that matter Resources: Barbell Medicine coaching and templates: https://www.barbellmedicine.com Plus podcast subscription: https://www.barbellmedicine.com/shop/subscriptions/plus-podcast-subscription/ Barbell Medicine Premium: https://www.barbellmedicine.com/shop/subscriptions/barbell-medicine-premium/ Signal (book pre-order): https://www.barbellmedicine.com/shop/learning/signal/ Our Protein Content: https://www.barbellmedicine.com/blog/protein-and-weight-loss/ https://www.barbellmedicine.com/blog/protein-on-ozempic/ https://www.barbellmedicine.com/blog/barbell-medicine-protein-recommendations/ StudiesLevine et al. Cell Metabolism 2014. doi:10.1016/j.cmet.2014.02.006Naghshi et al. BMJ 2020. doi:10.1136/bmj.m2412 Devries et al. J Nutr 2018. doi:10.1093/jn/nxy197 Antonio et al. J Nutr Metab 2016. doi:10.1155/2016/9104792 Knight et al. Ann Intern Med 2003. doi:10.7326/0003-4819-138-6-200303180-00009 Klahr et al. (MDRD). NEJM 1994. doi:10.1056/NEJM199403313301301 Hahn, Hodson & Fouque. Cochrane 2020. doi:10.1002/14651858.CD001892.pub5 Obeid, Hiremath & Topf. Kidney360 2022. doi:10.34067/KID.0001002022 Lew et al. J Am Soc Nephrol 2017. doi:10.1681/ASN.2016030248Castaneda et al. Ann Intern Med 2001. doi:10.7326/0003-4819-135-11-200112040-00008 Bauer et al. (PROT-AGE). JAMDA 2013. doi:10.1016/j.jamda.2013.05.021Fenton et al. Nutrition Journal 2011. doi:10.1186/1475-2891-10-41Shams-White et al. Am J Clin Nutr 2017. doi:10.3945/ajcn.116.145110Witard et al. Am J Clin Nutr 2013. doi:10.3945/ajcn.112.055517 Macnaughton et al. Physiol Rep 2016. doi:10.14814/phy2.12893Trommelen et al. Cell Reports Medicine 2023. doi:10.1016/j.xcrm.2023.101324 Wycherley et al. Am J Clin Nutr 2012. doi:10.3945/ajcn.112.044321 Moore et al. JAMA Intern Med 2016. doi:10.1001/jamainternmed.2016.1548 Larsson et al. Cancer Med 2020. doi:10.1002/cam4.3345 Brenner, Meyer & Hostetter. NEJM 1982. doi:10.1056/NEJM198209093071104 Chan et al. PLoS One 2011. doi:10.1371/journal.pone.0020456Berryman et al. Am J Clin Nutr 2018. doi:10.1093/ajcn/nqy088 Morton et al. Br J Sports Med 2018. doi:10.1136/bjsports-2017-097608 Advertising Inquiries: https://redcircle.com/brands

   July 24, 2026·33min
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4. 4
   Number 4: Is It Really Just Calories In, Calories Out? Metabolism, Insulin, Hormones and Why Counting Fails

   Is weight loss really just Calories in, Calories out? The equation is true, but "just count your Calories" is bad advice for most people, and almost every objection to it is pointing at something real. In part two of our energy balance series, Jordan Feigenbaum takes the biggest "it's not Calories, it's ___" claims (metabolism, thyroid, cortisol, PCOS, insulin, the type of food) and tests each against the best evidence. The verdict: none of them breaks the equation. Every one is a hand on a lever that moves Calories in or Calories out, not a hole in the math. In this episode: why your metabolism does not crash at 40, how small real metabolic adaptation actually is after weight loss, why hypothyroid weight is mostly water, what the cortisol and PCOS (now PMOS) data show, how absorption and cooking move Calories only at the edges, why even dietitians miscount their own intake, and why the carbohydrate-insulin model fails three tests, including the GLP-1 drugs that raise insulin and still produce the biggest weight loss we have ever approved. Part two of three: willpower, Calories in Calories out, then GLP-1 drugs. Next week: are GLP-1s cheating? Timestamps0:00 Is it really just calories in, calories out?0:18 The willpower episode and the through-line2:10 Thermodynamics: what sets both sides2:41 Your metabolism is three things4:05 Claim 1: my metabolism crashed4:24 No cliff at 40: the doubly labeled water study5:33 Real metabolic adaptation after weight loss6:56 Why your food diary lies7:49 Claim 2: it's my hormones8:07 Thyroid: mostly water9:36 Cortisol: explains about 1 percent11:12 PCOS is now PMOS13:06 Menopause14:18 Claim 3: a calorie isn't a calorie16:48 Absorption: nuts, cooking, eggs19:44 Why calorie counting fails21:12 Claim 4: it's not Calories, it's insulin22:02 Testing the carbohydrate-insulin model25:52 The GLP-1 drugs that should end it28:34 The whole list, claim by claim29:53 What to actually do30:42 Next week: are GLP-1s cheating? Resources: Barbell Medicine coaching and templates: https://www.barbellmedicine.com https://www.barbellmedicine.com/shop/subscriptions/plus-podcast-subscription/ https://www.barbellmedicine.com/shop/subscriptions/barbell-medicine-premium/ Signal book pre-order: https://www.barbellmedicine.com/shop/learning/signal/ Pontzer et al., Science 2021. https://doi.org/10.1126/science.abe5017 Muller et al., Am J Clin Nutr 2015. https://doi.org/10.3945/ajcn.115.109173 Lichtman et al., N Engl J Med 1992. https://doi.org/10.1056/NEJM199212313272701 Karmisholt et al., J Clin Endocrinol Metab 2011. https://doi.org/10.1210/jc.2010-1521 Lee et al., Endocr Pract 2014. https://doi.org/10.4158/EP14072.OR van der Valk et al., Obes Rev 2022. https://doi.org/10.1111/obr.13376 Nikokavoura et al., Diabetes Metab Syndr Obes 2015. https://doi.org/10.2147/DMSO.S85134 Greendale et al., JCI Insight 2019. https://doi.org/10.1172/jci.insight.124865 Lejeune et al., Am J Clin Nutr 2006. https://doi.org/10.1093/ajcn/83.1.89 Bray et al., JAMA 2012. https://doi.org/10.1001/jama.2011.1918 Novotny et al., Am J Clin Nutr 2012. https://doi.org/10.3945/ajcn.112.035782 Baer et al., J Nutr 2016. https://doi.org/10.3945/jn.115.217372 Baer et al., Br J Nutr 2012. https://doi.org/10.1017/S0007114511002649 Evenepoel et al., J Nutr 1998. https://doi.org/10.1093/jn/128.10.1716 Hall et al., Cell Metabolism 2019. https://doi.org/10.1016/j.cmet.2019.05.008 Champagne et al., J Am Diet Assoc 2002. https://doi.org/10.1016/S0002-8223(02)90316-0 Hall et al., Cell Metabolism 2015. https://doi.org/10.1016/j.cmet.2015.07.021 Wilding et al., N Engl J Med 2021. https://doi.org/10.1056/NEJMoa2032183 Jastreboff et al., N Engl J Med 2022. https://doi.org/10.1056/NEJMoa2206038 Advertising Inquiries: https://redcircle.com/brands

   July 17, 2026·32min
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5. 5
   Number 5: The Man Who Couldn’t Stop Gaining Weight | A Medical Mystery

   A previously healthy 21-year-old shows up with seven months of headaches and 30-plus pounds of weight gain he can’t explain. He’s eating the same and training more, and the scale climbs anyway. We hand the case to Dr. Austin Baraki cold and work it in real time: the exam, the labs, the MRI, and two diagnoses that turn a headache workup into the clearest proof we’ve got that body weight is set by the brain, not by character. This is the capstone of our weight series (willpower, calories, protein), and it ends on the drug that, this year, did something for these patients that nothing had done before. Timestamps00:00:00 Cold open: the man who couldn’t stop gaining weight00:01:49 Meet the case (and the rules of the game)00:02:36 The presentation: 21, headaches, unexplained weight gain00:03:57 Austin’s one-liner and how a clinician builds a differential00:05:10 Secondary headaches: what raises the red flag00:13:12 The exam: vitals, and the eye findings that matter00:14:37 The labs, one number at a time00:16:08 Raised pressure and a visual-field clue (bitemporal hemianopia)00:20:45 The MRI00:21:54 First diagnosis: craniopharyngioma00:25:32 The name: a tumor built from tooth tissue00:25:50 Surgery, and what it costs00:27:43 The new mystery: gaining weight faster than ever00:33:41 Second diagnosis: acquired hypothalamic obesity00:39:17 How your brain sets your weight: the POMC brake and the AgRP accelerator00:42:07 What about leptin?00:45:46 Monogenic vs common obesity00:50:30 Why GLP-1 drugs still worked: the brainstem backdoor00:52:11 Responders and non-responders00:55:40 Setmelanotide: a drug for the broken circuit00:56:53 TRANSCEND, and the new FDA approval00:58:55 What it costs01:01:32 Why we care about body fat at all: the garage01:04:36 Flux: which fat is actually dangerous01:09:15 Close Resources Barbell Medicine coaching and templates: https://www.barbellmedicine.com Plus podcast subscription: https://www.barbellmedicine.com/shop/subscriptions/plus-podcast-subscription/ Barbell Medicine Premium: https://www.barbellmedicine.com/shop/subscriptions/barbell-medicine-premium/ Signal (book pre-order): https://www.barbellmedicine.com/shop/learning/signal/ 1. Brijmohan A, et al. Acquired hypothalamic obesity following craniopharyngioma resection in a young adult [case report]. 2025. PMCID: PMC12268545; PMID: 40677794. 2. Miller JL, et al; TRANSCEND investigators. Setmelanotide in acquired hypothalamic obesity: a phase 3 randomized trial. N Engl J Med. 2026. 3. Rhythm Pharmaceuticals. FDA approves IMCIVREE (setmelanotide) for acquired hypothalamic obesity. News release. March 19, 2026. 4. US Food and Drug Administration. FDA approves first treatment for weight management for people with certain rare genetic conditions (setmelanotide). 2020. 5. Montague CT, Farooqi IS, Whitehead JP, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature. 1997;387(6636):903-908. 6. Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 1999;341(12):879-884. 7. Krude H, Biebermann H, Luck W, et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet. 1998;19(2):155-157. 8. Farooqi IS, Keogh JM, Yeo GS, et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003;348(12):1085-1095. 9. Clément K, Vaisse C, Lahlou N, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998;392(6674):398-401. 10. Fabbrini E, Tamboli RA, Magkos F, et al. Surgical removal of omental fat does not improve insulin sensitivity and cardiovascular risk factors in obese adults. Gastroenterology. 2010;139(2):448-455. 11. Klein S, Fontana L, Young VL, et al. Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. N Engl J Med. 2004;350(25):2549-2557. 12. Guyenet SJ. The Hungry Brain: Outsmarting the Instincts That Make Us Overeat. Flatiron Books; 2017. Advertising Inquiries: https://redcircle.com/brands

   July 31, 2026·1h 11min
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