Barbell Medicine Podcast

How much resistance training do you actually need, and is there a point where more stops helping? We trace the "lift weights twice a week" recommendation back to the 1989 study it came from, which found that three days beat two, and to the citation loop that turned it into a guideline anyway. Then we go through the evidence on whether lifting is dangerous, including the heart, injury rates, and the J-shaped mortality curve, and work out where the dose-response actually saturates for strength, muscle mass, bone mineral density, and how your body handles fuel.

The short answer is that almost every number in this literature marks where a benefit starts, and very little of it goes far enough to show where a benefit stops. We finish by writing the resistance training guideline the way we think it should be written, with target outcomes, a training dose, and testable targets.

Timestamps 

• 00:00 Where the "lift weights twice a week" rule came from 
• 04:18 What actually counts as resistance training 
• 06:56 Does lifting make your heart wall thicker 
• 15:34 Anabolic steroids and the heart 
• 19:16 Injury rates and cardiac arrest at the gym 
• 22:03 How the lifting J-curve got made 
• 28:05 ACSM audits its own recommendation 
• 31:11 Strength: where the plateau actually sits 
• 35:49 Why grip strength can't answer this 
• 41:43 Muscle mass versus muscle function 
• 44:50 Bone, and the turkey wing that settled the dose 
• 49:50 Fuel handling, insulin sensitivity, and the clock 
• 1:00:46 The 2018 guidelines, and how I would write them
• 
  

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

Get early access, ad-free listening, and exclusive content here: https://barbellmedicine.supercast.com/

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Nearly every warning you've heard about lifting weights was written down before anybody checked it. We trace where those warnings came from, starting with a Harvard student in 1854 and ending with a curve on a graph that's being used today to argue you can lift too much.

Along the way: the men who built themselves with barbells and then sold the public five-pound dumbbells, because iron was expensive to mail and a booklet cost pennies. The muscle-bound myth, which nobody could define when a graduate student surveyed 45 physiologists about it. The 1961 report that took the deep squat out of every branch of the American military, measured with a device its author built himself and never validated. The claim that lifting stunts a child's growth, which no professional body ever actually made. And the argument women got, which was never about injury at all.

Timestamps:

• 0:00 Intro
• 2:33 2,500 years of people picking up heavy things
• 7:24 George Windship and the Health Lift
• 10:56 Blaikie's truck horse and the muscle-bound myth
• 14:59 Bernarr Macfadden
• 19:39 Charles Atlas and Dynamic Tension
• 27:01 Carl Klein, a homemade device, and the parallel squat
• 30:57 Thomas Delorme and three sets of ten
• 35:20 Kids, growth plates, and where the stunting idea came from
• 41:43 Women, "you'll get bulky," and Dudley Sargent in 1912
• 50:05 Pregnancy, from 1949 to a 2025 barbell study
• 53:40 The pattern, and the curve on next week's graph

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

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80. Faigenbaum AD. Youth resistance training. President's Council on Physical Fitness and Sports Research Digest. 2003;4(3):1-8.

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82. Rowe PH. Colles fracture due to weightlifting. Br J Sports Med. 1979;13(3):130-131. doi:10.1136/bjsm.13.3.130. PMID 486885.

83. Ryan JR, Salciccioli GG. Fractures of the distal radial epiphysis in adolescent weight lifters. Am J Sports Med. 1976;4(1):26-27. doi:10.1177/036354657600400105.

84. Benton JW. Epiphyseal fracture in sports. Physician Sportsmed. 1982;10(11):63-71.

85. Gumbs VL, Segal D, Halligan JB, Lower G. Bilateral distal radius and ulnar fractures in adolescent weight lifters. Am J Sports Med. 1982;10(6):375-379. doi:10.1177/036354658201000612.

86. Jenkins NH, Mintowt-Czyz WJ. Bilateral fracture separations of the distal radial epiphyses during weight-lifting. Br J Sports Med. 1986;20(2):72-73. doi:10.1136/bjsm.20.2.72.

87. Weiss AC, Sponseller PD. Salter-Harris type I fracture of the distal radius due to weightlifting. Orthop Rev. 1989;18(3):233-235.

88. Browne TD. Bilateral wrist fractures in an adolescent weightlifter. Orthopedics. 1990.

89. Faigenbaum AD, Myer GD. Resistance training among young athletes: safety, efficacy and injury prevention effects. Br J Sports Med. 2010;44(1):56-63. doi:10.1136/bjsm.2009.068098.

90. Sadres E, Eliakim A, Constantini N, Lidor R, Falk B. The effect of long-term resistance training on anthropometric measures, muscle strength, and self concept in pre-pubertal boys. Pediatr Exerc Sci. 2001;13(4):357-372. doi:10.1123/pes.13.4.357.

91. Malina RM. Weight training in youth: growth, maturation, and safety: an evidence-based review. Clin J Sport Med. 2006;16(6):478-487. doi:10.1097/01.jsm.0000248843.31874.be.

92. Lloyd RS, Faigenbaum AD, Stone MH, et al. Position statement on youth resistance training: the 2014 international consensus. Br J Sports Med. 2014;48(7):498-505. doi:10.1136/bjsports-2013-092952.

93. American Academy of Pediatrics Council on Sports Medicine and Fitness. Strength training by children and adolescents. Pediatrics. 2008;121(4):835-840. doi:10.1542/peds.2007-3790. PMID 18381549.

94. Faigenbaum AD, Kraemer WJ, Blimkie CJR, et al. Youth resistance training: updated position statement paper from the National Strength and Conditioning Association. J Strength Cond Res. 2009;23(5 Suppl):S60-S79. doi:10.1519/JSC.0b013e31819df407. PMID 19620931.

95. Milone MT, Bernstein J, Freedman KB, Tjoumakaris F. There is no need to avoid resistance training (weight lifting) until physeal closure. Phys Sportsmed. 2013;41(4):101-105. doi:10.3810/psm.2013.11.2040. PMID 24393806.

96. Fiatarone MA, Marks EC, Ryan ND, Meredith CN, Lipsitz LA, Evans WJ. High-intensity strength training in nonagenarians: effects on skeletal muscle. JAMA. 1990;263(22):3029-3034. PMID 2342214.

97. Fiatarone MA, O'Neill EF, Ryan ND, et al. Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med. 1994;330(25):1769-1775. doi:10.1056/NEJM199406233302501. PMID 8190152.

98. Sargent DA. Are athletics making girls masculine? A practical answer to a question every girl asks. 1912.

99. Jones A. Weight-training for women. In: Nautilus Bulletin No. 2. Ch. 15. DeLand, FL: Nautilus Sports/Medical Industries; [c1971]. http://www.arthurjonesexercise.com/Bulletin2/15.PDF.

100. Cureton KJ, Collins MA, Hill DW, McElhannon FM. Muscle hypertrophy in men and women. Med Sci Sports Exerc. 1988;20(4):338-344. PMID 3173042.

101. Hubal MJ, Gordish-Dressman H, Thompson PD, et al. Variability in muscle size and strength gain after unilateral resistance training. Med Sci Sports Exerc. 2005;37(6):964-972. PMID 15947721.

102. Roberts BM, Nuckols G, Krieger JW. Sex differences in resistance training: a systematic review and meta-analysis. J Strength Cond Res. 2020;34(5):1448-1460. doi:10.1519/JSC.0000000000003521. PMID 32218059.

103. Refalo MC, Nuckols G, Galpin AJ, Gallagher IJ, Hamilton DL, Fyfe JJ. Sex differences in absolute and relative changes in muscle size following resistance training in healthy adults: a systematic review with Bayesian meta-analysis. PeerJ. 2025;13:e19042. doi:10.7717/peerj.19042. PMID 40028215.

104. Handelsman DJ, Hirschberg AL, Bermon S. Circulating testosterone as the hormonal basis of sex differences in athletic performance. Endocr Rev. 2018;39(5):803-829. doi:10.1210/er.2018-00020. PMID 30010735.

105. Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 1996;335(1):1-7. doi:10.1056/NEJM199607043350101. PMID 8637535.

106. Huang G, Basaria S, Travison TG, et al. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy. Menopause. 2014;21(6):612-623. doi:10.1097/GME.0000000000000093. PMID 24281237.

107. Franke WW, Berendonk B. Hormonal doping and androgenization of athletes: a secret program of the German Democratic Republic government. Clin Chem. 1997;43(7):1262-1279. PMID 9216474.

108. OpenPowerlifting database analysis of tested versus untested totals.

109. Average player heights, National Basketball Association and Women's National Basketball Association, against US adult means from the National Health and Nutrition Examination Survey anthropometric reference data.

110. History of women's weightlifting. International Weightlifting Federation. Accessed September 2026. https://iwf.sport.

111. Adamfi A, IWF Director General, on the pre-1983 IWF constitution. Inside the Games. Accessed September 2026. https://www.insidethegames.biz.

112. History of women's powerlifting. International Powerlifting Federation. Accessed September 2026. https://www.powerlifting.sport.

113. Holloway JB, Gater D, Ritchie M, et al. Strength training for female athletes: a position paper. Part I. NSCA J. 1989;11(4):43-51. Part II. NSCA J. 1989;11(5):29-36.

114. Kehler AK, Heinrich KM. A selective review of prenatal exercise guidelines since the 1950s until present: written for women, health care professionals, and female athletes. Women Birth. 2015;28(4):e93-e98. doi:10.1016/j.wombi.2015.07.004. PMID 26210535.

115. Berghella V, Saccone G. Exercise in pregnancy! Am J Obstet Gynecol. 2017;216(4):335-337. doi:10.1016/j.ajog.2017.01.023.

116. Davenport MH, Ruchat SM, Poitras VJ, et al. Prenatal exercise for the prevention of gestational diabetes mellitus and hypertensive disorders of pregnancy: a systematic review and meta-analysis. Br J Sports Med. 2018;52(21):1367-1375. doi:10.1136/bjsports-2018-099355. PMID 30337463.

117. Prevett C, Gingerich J, Sivak A, Davenport MH. Impact of resistance training on maternal and fetal outcomes: a systematic review and meta-analysis. Br J Sports Med. 2025;59(17):1173-1183. doi:10.1136/bjsports-2025-109626. PMID 40610191.

118. Moolyk AN, Wowdzia JB, Matenchuk BA, et al. Acute fetal response to high-intensity resistance training in pregnancy. Br J Sports Med. 2025;59(3):159-167. doi:10.1136/bjsports-2024-108569. PMID 39694629.

119. Momma H, Kawakami R, Honda T, Sawada SS. Muscle-strengthening activities are associated with lower risk and mortality in major non-communicable diseases: a systematic review and meta-analysis of cohort studies. Br J Sports Med. 2022;56(13):755-763. doi:10.1136/bjsports-2021-105061.

120. Bennie JA, Lee DC, Khan A, et al. Muscle-strengthening exercise among 397,423 U.S. adults: prevalence, correlates, and associations with health conditions. Am J Prev Med. 2018;55(6):864-874. doi:10.1016/j.amepre.2018.07.022. PMID 30458949.

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Parts of the country now get a few weeks of wildfire smoke every year, and the obvious question is whether there is a point where the air is bad enough that the workout costs you more than it gives you. We went and looked. There is a real number, it comes from about 1.5 million people, and it is not the number that gets quoted.

This is a free preview of Direct Line, our monthly ask-us-anything for Barbell Medicine Plus subscribers. Two of this month's twelve questions are here in full.

First: training in wildfire smoke. What PM2.5 is, why the AQI on your phone and the number in the paper are not the same quantity, where the 90-minutes-at-100-micrograms figure comes from and why it is softer than it sounds, what happened when six cities modeled telling people to stay inside, and why your breathing rate during a set of squats matters more than you would think.

Second: the effective reps model. A subscriber noticed that if a set only counts when you are within five reps of failure, the triceps in a heavy bench press should not count, and if you are going to count that as a fractional set for the triceps, then a warm-up set counts for the chest. Both cannot be true. We go through the meta-regression on proximity to failure, the 67-study analysis that tested whether an indirect set should count as one, as half, or as zero, and where we actually put our sets.

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Timestamps

• 1:47 The question: is there a point where the air is too bad to train?
• 2:37 What PM2.5 actually is
• 3:05 AQI vs micrograms, and why your phone disagrees with the paper
• 3:50 Where the "90 minutes" number comes from
• 4:54 Austin: what breathing this air does to your lungs
• 9:14 1.5 million adults: does dirty air cancel the benefit of exercise?
• 10:44 Six cities modeled staying indoors. Mortality did not improve.
• 11:22 Lifting vs cycling: breathing rate is the whole mechanism
• 12:33 Indoor air during a wildfire, and what filtration does not fix
• 13:24 Is wildfire smoke worse than city pollution?
• 14:38 What we would actually tell a patient
• 18:35 The question: hard sets, fractional sets, and the five-rep rule
• 19:18 Reps in reserve, hard sets, and fractional sets defined
• 20:19 The meta-regression: no threshold, just a line
• 21:13 Do indirect sets count as half a set?
• 23:08 Would you rather: every set at 5 RIR, or every set to failure?
• 25:22 Why you get worse at judging RIR the further you are from failure
• 28:42 The numbers we use: RPE 7 to 9 for hypertrophy, 4 to 6 for strength
• 29:20 Austin: individual variation dwarfs all of this
• 33:28 Why nobody can measure training load in the weight room

Resources

Tainio M, de Nazelle AJ, Götschi T, et al. Can air pollution negate the health benefits of cycling and walking? Prev Med. 2016;87:233-236. doi:10.1016/j.ypmed.2016.02.002. PMID 27156248

Ku PW, Steptoe A, Hamer M, et al. Does ambient PM2.5 reduce the protective association of leisure-time physical activity with mortality? A systematic review, meta-analysis, and individual-level pooled analysis of cohort studies involving 1.5 million adults. BMC Med. 2025;23(1):647. doi:10.1186/s12916-025-04496-y. PMID 41310726

Giallouros G, Kouis P, Papatheodorou SI, Woodcock J, Tainio M. The long-term impact of restricting cycling and walking during high air pollution days on all-cause mortality: health impact assessment study. Environ Int. 2020;140:105679. doi:10.1016/j.envint.2020.105679. PMID 32353667

Sun S, Cao W, Qiu H, et al. Benefits of physical activity not affected by air pollution: a prospective cohort study. Int J Epidemiol. 2020;49(1):142-152. doi:10.1093/ije/dyz184. PMID 31504557

Robles P, Araujo T, Brooks D, et al. Cardiorespiratory responses to short bouts of resistance training exercises in individuals with chronic obstructive pulmonary disease: a comparison of exercise intensities. J Cardiopulm Rehabil Prev. 2017;37(5):356-362. doi:10.1097/HCR.0000000000000282. PMID 28858033

Liang Y, Sengupta D, Campmier MJ, Lunderberg DM, Apte JS, Goldstein AH. Wildfire smoke impacts on indoor air quality assessed using crowdsourced data in California. Proc Natl Acad Sci U S A. 2021;118(36):e2106478118. doi:10.1073/pnas.2106478118. PMID 34465624

Aguilera R, Corringham T, Gershunov A, Benmarhnia T. Wildfire smoke impacts respiratory health more than fine particles from other sources: observational evidence from Southern California. Nat Commun. 2021;12(1):1493. doi:10.1038/s41467-021-21708-0. PMID 33674571

US Environmental Protection Agency. Air Quality Index (AQI) breakpoints. Air Quality System code tables. Accessed August 10, 2026. https://aqs.epa.gov/aqsweb/documents/codetables/aqi_breakpoints.html

Robinson ZP, Pelland JC, Remmert JF, Refalo MC, Jukic I, Steele J, et al. Exploring the dose-response relationship between estimated resistance training proximity to failure, strength gain, and muscle hypertrophy: a series of meta-regressions. Sports Med. 2024;54(9):2209-2231. doi:10.1007/s40279-024-02069-2. PMID 38970765

Pelland JC, Remmert JF, Robinson ZP, Hinson SR, Zourdos MC. The resistance training dose response: meta-regressions exploring the effects of weekly volume and frequency on muscle hypertrophy and strength gains. Sports Med. 2026;56(2):481-505. doi:10.1007/s40279-025-02344-w

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Most lifters have been told they need to eat in a Calorie surplus to build muscle. That rule has always come with a list of exceptions: unless you're new, unless you're carrying extra body fat, unless you're coming back from time off. Dr. Eric Helms joins Dr. Jordan Feigenbaum to work out what the rule is actually tracking, starting from a question with a real number attached: what does a pound of muscle cost to build? And then, do you need to be in a surplus to build muscle? 

Timestamps:

• 0:00 The rule, and its exceptions
• 2:08 Where "you need a surplus" came from
• 7:12 Heuristics versus theories
• 11:40 Hypertrophy, maintenance, deficit and surplus defined
• 14:58 Body fat as a savings account
• 18:24 How fast anyone can actually build muscle
• 23:39 What sets the ceiling: stimulus, not genetics
• 26:37 Microgravity, astronauts, and a 20 kg barbell
• 31:49 What constrains growth if steroids don't break the ceiling
• 36:44 If training sets the ceiling, what does energy do
• 38:45 What 1 kg of muscle costs to build
• 44:05 Why 3,500 Calories doesn't tell you what to eat
• 44:55 REDs and the dual intervention model
• 47:51 The 2000s bulking studies
• 51:34 Garthe 2013: elite athletes and a 500 Calorie surplus
• 58:30 Protein: 1.6 versus 2.5 g/kg
• 1:03:31 What starvation research shows the body protects
• 1:10:29 Vargas-Molina: maintenance versus deficit
• 1:19:17 What to do if you're lean
• 1:39:34 What would prove this wrong
• 1:57:57 Three buckets

Resources:

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1. Nikolaidis MG, Paschalis V, Margaritelis NV. The energetic cost of building human skeletal muscle. bioRxiv. Preprint posted online August 17, 2026. doi:10.64898/2026.08.17.745156
2. Rozenek R, Ward P, Long S, Garhammer J. Effects of high-calorie supplements on body composition and muscular strength following resistance training. J Sports Med Phys Fitness. 2002;42(3):340-347.
3. Garthe I, Raastad T, Refsnes PE, Koivisto A, Sundgot-Borgen J. Effect of two different weight-loss rates on body composition and strength and power-related performance in elite athletes. Int J Sport Nutr Exerc Metab. 2011;21(2):97-104.
4. Garthe I, Raastad T, Refsnes PE, Sundgot-Borgen J. Effect of nutritional intervention on body composition and performance in elite athletes. Eur J Sport Sci. 2013;13(3):295-303. doi:10.1080/17461391.2011.643923
5. Helms ER, Zinn C, Rowlands DS, Brown SR. A systematic review of dietary protein during caloric restriction in resistance trained lean athletes: a case for higher intakes. Int J Sport Nutr Exerc Metab. 2014;24(2):127-138. doi:10.1123/ijsnem.2013-0054
6. Slater GJ, Dieter BP, Marsh DJ, Helms ER, Shaw G, Iraki J. Is an energy surplus required to maximize skeletal muscle hypertrophy associated with resistance training. Front Nutr. 2019;6:131. doi:10.3389/fnut.2019.00131
7. 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
8. Helms ER, Spence A, 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
9. Mountjoy M, Ackerman KE, Bailey DM, et al. 2023 International Olympic Committee's (IOC) consensus statement on Relative Energy Deficiency in Sport (REDs). Br J Sports Med. 2023;57(17):1073-1097. doi:10.1136/bjsports-2023-106994
10. Speakman JR, Hall KD. Models of body weight and fatness regulation. Philos Trans R Soc Lond B Biol Sci. 2023;378(1888):20220231. doi:10.1098/rstb.2022.0231
11. Vargas-Molina S, García-Palumbo A, García-Sillero M, et al. Comparison of two nutritional protocols in body re-composition of resistance-trained participants. Eur J Appl Physiol. 2026;126(7):4019-4030. doi:10.1007/s00421-026-06209-6

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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. 

Timestamps

• 0:00   The one-leg study, and the muscle-centric claim
• 02:06   What obesity is, and the garage analogy
• 05:06   How glucose gets into a muscle cell
• 11:21   Insulin sensitivity improves without building muscle
• 17:11   The best case for muscle-centric medicine
• 21:13   What predicts falls and death: strength, not lean mass
• 25:18   Separating muscle size from muscle function
• 31:33   Liver fat: amount, type, and flux
• 37:54   Should you build muscle first? The arithmetic
• 42:37   Building muscle in a calorie deficit
• 50:29   GLP-1s, DXA, and the lean mass panic
• 58:23   Sarcopenic obesity, and why the name is wrong
• 01:04:37 Why size still tells you something
• 01:11:46 So what is obesity?

Resources:

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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

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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

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16. Wenker 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.12890
17. Basaria 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/NEJMoa1000485
18. Vigen 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.2013.280386
19. Basaria 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.2015.8881
20. Budoff 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.2016.21043
21. Lincoff 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/NEJMoa2215025
22. Huggins 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.
23. 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.2008.09.024
24. Khera 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.2013.08.015
25. Bhasin 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.2023.48692
26. Snyder 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

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In 2004 a surgeon removed about ten kilograms of fat from fifteen women and measured everything that mattered. Nothing improved. Four years later, it still hadn't.

That result should have ended an argument about body fat. Instead the argument got more specific, and the version you've heard most recently is that visceral fat, the fat around your organs, is the dangerous kind. I've said a version of that myself on this show, and in this episode I expand upon it.

This one starts from the beginning: what your fat is actually for, what insulin is, and what insulin resistance means, in plain terms and assuming nothing. Then four experiments that all point the same direction. Fat removed surgically, and the disease doesn't follow. People born with no fat tissue at all, who get the entire disease anyway. A hormone that reversed a 48% fatty liver without adding a gram of fat. And a diabetes drug that made people heavier and healthier at the same time.

The second half is practical. What a fatty liver actually does over twenty years, what BMI can and can't do, why the Lancet Commission changed the definition of obesity in 2025, and the exact order of tests I'd use, including the TyG index, FIB-4, and where each one stops working.

Part one of two. Next episode is about muscle.

Timestamps:

00:00 The Liposuction Experiment

02:06 The Visceral Fat Correction

05:47 What Fat Is For

08:14 The Carb Insulin Model

10:51 Filling The Garage

14:35 Taking The Fat Out

17:57 Born Without Fat Tissue

22:52 Heavier And Healthier

25:05 Neptune And Vulcan

29:57 The Patient Nobody Checked

33:59 What Every Ruler Missed

36:00 What To Actually Order

40:29 What Obesity Actually Is

Resources:

Vital 5 (TyG , waist to height, etc. discussion):

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1. 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. doi:10.1056/NEJMoa033179
2. Mohammed BS, Cohen S, Reeds D, Young VL, Klein S. Long-term effects of large-volume liposuction on metabolic risk factors for coronary heart disease. Obesity (Silver Spring). 2008;16(12):2648-2651. doi:10.1038/oby.2008.418
3. Sommer I, Teufer B, Szelag M, et al. The performance of anthropometric tools to determine obesity: a systematic review and meta-analysis. Sci Rep. 2020;10(1):12699. doi:10.1038/s41598-020-69498-7
4. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1343-1351. doi:10.1172/JCI23621
5. Spalding KL, Arner E, Westermark PO, et al. Dynamics of fat cell turnover in humans. Nature. 2008;453(7196):783-787. doi:10.1038/nature06902
6. 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. doi:10.1053/j.gastro.2010.04.056
7. Garg A. Acquired and inherited lipodystrophies. N Engl J Med. 2004;350(12):1220-1234. doi:10.1056/NEJMra025261
8. Al Yaarubi S, Alsagheir A, Al Shidhani A, et al. Analysis of disease characteristics of a large patient cohort with congenital generalized lipodystrophy from the Middle East and North Africa. Orphanet J Rare Dis. 2024;19(1):118. doi:10.1186/s13023-024-03084-2
9. Petersen KF, Oral EA, Dufour S, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest. 2002;109(10):1345-1350. doi:10.1172/JCI200215001
10. Miyazaki Y, Mahankali A, Matsuda M, et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab. 2002;87(6):2784-2791. doi:10.1210/jcem.87.6.8567
11. Cusi K, Orsak B, Bril F, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med. 2016;165(5):305-315. doi:10.7326/M15-1774
12. Taylor R, Barnes AC, Hollingsworth KG, et al. Aetiology of type 2 diabetes in people with a 'normal' body mass index: testing the personal fat threshold hypothesis. Clin Sci (Lond). 2023;137(16):1333-1346. doi:10.1042/CS20230586
13. Martin S, Cule M, Basty N, et al. Genetic evidence for different adiposity phenotypes and their opposing influences on ectopic fat and risk of cardiometabolic disease. Diabetes. 2021;70(8):1843-1856. doi:10.2337/db21-0129
14. Martin S, Sorokin EP, Thomas EL, et al. Estimating the effect of liver and pancreas volume and fat content on risk of diabetes: a Mendelian randomization study. Diabetes Care. 2022;45(2):460-468. doi:10.2337/dc21-1262
15. Sanyal AJ, Kaplan LM, Frias JP, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med. 2024;30(7):2037-2048. doi:10.1038/s41591-024-03018-2
16. Portillo-Sanchez P, Bril F, Maximos M, et al. High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J Clin Endocrinol Metab. 2015;100(6):2231-2238. doi:10.1210/jc.2015-1966
17. Hagström H, Nasr P, Ekstedt M, et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017;67(6):1265-1273. doi:10.1016/j.jhep.2017.07.027
18. Rubino F, Cummings DE, Eckel RH, et al. Definition and diagnostic criteria of clinical obesity. Lancet Diabetes Endocrinol. 2025;13(3):221-262. doi:10.1016/S2213-8587(24)00316-4
19. Guerrero-Romero F, Simental-Mendía LE, González-Ortiz M, et al. The product of triglycerides and glucose, a simple measure of insulin sensitivity: comparison with the euglycemic-hyperinsulinemic clamp. J Clin Endocrinol Metab. 2010;95(7):3347-3351. doi:10.1210/jc.2010-0288
20. Sánchez-García A, Rodríguez-Gutiérrez R, Mancillas-Adame L, et al. Diagnostic accuracy of the triglyceride and glucose index for insulin resistance: a systematic review. Int J Endocrinol. 2020;2020:4678526. doi:10.1155/2020/4678526
21. McLaughlin T, Abbasi F, Cheal K, Chu J, Lamendola C, Reaven G. Use of metabolic markers to identify overweight individuals who are insulin resistant. Ann Intern Med. 2003;139(10):802-809. doi:10.7326/0003-4819-139-10-200311180-00007
22. McPherson S, Hardy T, Dufour JF, et al. Age as a confounding factor for the accurate non-invasive diagnosis of advanced NAFLD fibrosis. Am J Gastroenterol. 2017;112(5):740-751. doi:10.1038/ajg.2016.453
23. Mózes FE, Lee JA, Selvaraj EA, et al. Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis. Gut. 2022;71(5):1006-1019. doi:10.1136/gutjnl-2021-324243
24. 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
25. 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
26. Wildman RP, Muntner P, Reynolds K, et al. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999-2004). Arch Intern Med. 2008;168(15):1617-1624. doi:10.1001/archinte.168.15.1617
27. Mongraw-Chaffin M, Foster MC, Anderson CAM, et al. Metabolically healthy obesity, transition to metabolic syndrome, and cardiovascular risk. J Am Coll Cardiol. 2018;71(17):1857-1865. doi:10.1016/j.jacc.2018.02.055
28. Gujral UP, Vittinghoff E, Mongraw-Chaffin M, et al. Cardiometabolic abnormalities among normal-weight persons from five racial/ethnic groups in the United States: a cross-sectional analysis of two cohort studies. Ann Intern Med. 2017;166(9):628-636. doi:10.7326/M16-1895
29. Ruderman NB, Schneider SH, Berchtold P. The "metabolically-obese," normal-weight individual. Am J Clin Nutr. 1981;34(8):1617-1621. doi:10.1093/ajcn/34.8.1617
30. Sims EA. Are there persons who are obese, but metabolically healthy? Metabolism. 2001;50(12):1499-1504. doi:10.1053/meta.2001.27213
31. National Heart, Lung, and Blood Institute. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: The Evidence Report. NIH Publication 98-4083. Bethesda, MD: National Institutes of Health; September 1998.
32. American Medical Association House of Delegates. Resolution 420 (A-13): Recognition of Obesity as a Disease. Adopted June 18, 2013.
33. American Medical Association Council on Science and Public Health. Report 3-A-13: Is Obesity a Disease? 2013.
34. Rey-López JP, de Rezende LF, Pastor-Valero M, Tess BH. The prevalence of metabolically healthy obesity: a systematic review and critical evaluation of the definitions used. Obes Rev. 2014;15(10):781-790. doi:10.1111/obr.12198
35. Hinnouho GM, Czernichow S, Dugravot A, Batty GD, Kivimaki M, Singh-Manoux A. Metabolically healthy obesity and risk of mortality: does the definition of metabolic health matter? Diabetes Care. 2013;36(8):2294-2300. doi:10.2337/dc12-1654
36. Herman WH, Ye W, Griffin SJ, et al. Early detection and treatment of type 2 diabetes reduce cardiovascular morbidity and mortality: a simulation of the results of the Anglo-Danish-Dutch study of intensive treatment in people with screen-detected diabetes in primary care (ADDITION-Europe). Diabetes Care. 2015;38(8):1449-1455. doi:10.2337/dc14-2459
37. Le MH, Yeo YH, Cheung R, Wong VW, Nguyen MH. Ethnic influence on nonalcoholic fatty liver disease prevalence and lack of disease awareness in the United States, 2011-2016. J Intern Med. 2020;287(6):711-722. doi:10.1111/joim.13035
38. Sutin AR, Stephan Y, Terracciano A. Weight discrimination and risk of mortality. Psychol Sci. 2015;26(11):1803-1811. doi:10.1177/0956797615601103
39. Amy NK, Aalborg A, Lyons P, Keranen L. Barriers to routine gynecological cancer screening for White and African-American obese women. Int J Obes (Lond). 2006;30(1):147-155. doi:10.1038/sj.ijo.0803105
40. Kramer CK, Zinman B, Retnakaran R. Are metabolically healthy overweight and obesity benign conditions? A systematic review and meta-analysis. Ann Intern Med. 2013;159(11):758-769. doi:10.7326/0003-4819-159-11-201312030-00008

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A popular paper claimed the longevity benefit of lifting disappears once you train more than an hour a week. It's a real paper, but the claim is a misread. This is the free cut of this month's Direct Line, where Drs. Feigenbaum and Baraki also take on whether GLP-1s affect your mood, the "same calories, more weight loss" protein argument, and what you can actually do in the gym when you have chronic fatigue syndrome.

For education and infotainment, not medical advice.

To become a member and have us answer YOUR questions, join today:

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Timestamps:

0:00 Intro

0:38 The paper: does lifting stop helping after an hour?

3:19 The newer 147,000-person, 30-year study

13:21 GLP-1s, mood, and motivation

14:50 The FDA reverses the suicide warning

19:29 What happened when they gave people a GLP-1 in a bar

24:54 Is a calorie just a calorie?

28:17 The "same calories, more weight loss" protein study

30:48 Does keto break the laws of physics?

34:56 Lifting with chronic fatigue syndrome

36:14 The identical-twin experiment

37:36 Can lifting in bed do anything?

45:33 Get the full Direct Line

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1. Momma H, Kawakami R, Honda T, Sawada SS. Muscle-strengthening activities are associated with lower risk and mortality in major non-communicable diseases: a systematic review and meta-analysis of cohort studies. *Br J Sports Med*. 2022;56(13):755-763. doi:10.1136/bjsports-2021-105061

2. Dankel SJ, Loenneke JP, Loprinzi PD. Dose-dependent association between muscle-strengthening activities and all-cause mortality: prospective cohort study among a national sample of adults in the USA. *Arch Cardiovasc Dis*. 2016;109(11):626-633. doi:10.1016/j.acvd.2016.04.005

3. Zhang Y, Lee DH, Rezende LFM, Ma Y, Giovannucci E. Long-term resistance training with all-cause and cause-specific mortality: assessing dose-response and joint associations with aerobic physical activity. *Br J Sports Med*. Published online June 2, 2026. doi:10.1136/bjsports-2025-110503

4. US Food and Drug Administration. FDA requests removal of suicidal behavior and ideation warning from glucagon-like peptide-1 receptor agonist (GLP-1 RA) medications. Drug Safety Communication. January 13, 2026. Accessed August 12, 2026. https://www.fda.gov/drugs/drug-safety-communications/fda-requests-removal-suicidal-behavior-and-ideation-warning-glucagon-peptide-1-receptor-agonist-glp

5. Hendershot CS, Bremmer MP, Paladino MB, et al. Once-weekly semaglutide in adults with alcohol use disorder: a randomized clinical trial. *JAMA Psychiatry*. 2025;82(4):395-405. doi:10.1001/jamapsychiatry.2024.4789

6. Klausen MK, Justesen SK, Pedersen JN, et al. Once-weekly semaglutide versus placebo in patients with alcohol use disorder and comorbid obesity: a randomised, double-blind, placebo-controlled trial. *Lancet*. 2026;407(10540):1687-1698. doi:10.1016/S0140-6736(26)00305-3

7. Haghighat N, Ashtary-Larky D, Bagheri R, et al. The effect of 12 weeks of euenergetic high-protein diet in regulating appetite and body composition of women with normal-weight obesity: a randomised controlled trial. *Br J Nutr*. 2020;124(10):1044-1051. doi:10.1017/S0007114520002019

8. Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Board on the Health of Select Populations, Institute of Medicine. *Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness*. National Academies Press; 2015. Accessed August 12, 2026. https://www.ncbi.nlm.nih.gov/books/NBK274235/

9. Giloteaux L, Hanson MR, Keller BA. A pair of identical twins discordant for myalgic encephalomyelitis/chronic fatigue syndrome differ in physiological parameters and gut microbiome composition. *Am J Case Rep*. 2016;17:720-729. doi:10.12659/AJCR.900314

10. Rangan A, Brealey SD, Keding A, et al. Management of adults with primary frozen shoulder in secondary care (UK FROST): a multicentre, pragmatic, three-arm, superiority randomised clinical trial. *Lancet*. 2020;396(10256):977-989. doi:10.1016/S0140-6736(20)31965-6

11. Millar NL, Meakins A, Struyf F, et al. Frozen shoulder. *Nat Rev Dis Primers*. 2022;8(1):59. doi:10.1038/s41572-022-00386-2

12. US Department of Agriculture, US Department of Health and Human Services. *Dietary Guidelines for Americans, 2025-2030*. January 2026. Accessed August 12, 2026. https://www.dietaryguidelines.gov/

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An FDA advisory committee just voted to open a legal compounding supply line for six of seven peptides, including BPC-157 and TB-500, over the objection of the FDA's own scientists, who recommended against all seven. Dr. Jordan Feigenbaum walks through what the Pharmacy Compounding Advisory Committee actually voted on, why a vote about ulcerative colitis ends up governing tendon and joint use, what the single human BPC-157 trial does and doesn't show, and why "a pharmacy makes it safe" and "there's no money to study it" don't hold up. Evidence-based, no hype, no nocebo.

Timestamps:

 | 00:00:00 | The FDA voted 8-6. What it actually means

 | 00:01:25 | What I am, and am not, claiming

 | 00:03:21 | How they got here: Category 2 and the paperwork

 | 00:07:17 | Who was in the room: the panel that flipped

 | 00:10:57 | What they voted on: compounding and the bulks list

 | 00:15:37 | "No money in it, you can't patent it"

 | 00:18:24 | The trials already run: Plevna and MK-677

 | 00:22:55 | "I took it and it worked": placebo and fake surgery

 | 00:27:02 | The one human trial: Ruenzi 2005

 | 00:32:28 | Is it natural? Is it even a drug?

 | 00:36:58 | Harm reduction, or follow the money?

 | 00:42:45 | Three times a missing trial went wrong

 | 00:50:58 | Safety: known, unknown, and unknowable

 | 00:55:22 | The other six peptides

 | 00:58:22 | What I'd actually tell you

 | 01:02:08 | What actually works, and what would change my mind

Resources:

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1. US Food and Drug Administration. FDA Briefing Document: Pharmacy Compounding Advisory Committee Meeting. July 23-24, 2026. Silver Spring, MD: FDA; 2026.

2. US Food and Drug Administration. FDA review of BPC-157-related bulk drug substances. PCAC Briefing Document. July 23-24, 2026. Media 193343. Accessed July 24, 2026. https://www.fda.gov/media/193343/download

3. US Food and Drug Administration. FDA review of TB-500-related bulk drug substances. PCAC Briefing Document. July 23-24, 2026. Media 193349.

4. US Food and Drug Administration. FDA review of KPV-, MOTS-c-, Semax-, Epitalon-, and Emideltide-related bulk drug substances. PCAC Briefing Documents. July 23-24, 2026.

5. US Food and Drug Administration. Questions for the Pharmacy Compounding Advisory Committee. July 23-24, 2026.

6. US Food and Drug Administration. Pharmacy Compounding Advisory Committee meeting roster. July 23-24, 2026. Media 193772.

7. US Food and Drug Administration. Pharmacy Compounding Advisory Committee meeting roster. 2022. Media 159040.

8. openFDA. FAERS adverse event reports for BPC-157. Accessed July 24, 2026. https://open.fda.gov

9. Pharmacy compounding; 503A bulk drug substances. 21 CFR §216.23 (2026).

10. Federal Food, Drug, and Cosmetic Act §503A, 21 USC §353a (pharmacy compounding).

11. Abigail Alliance for Better Access to Developmental Drugs v von Eschenbach, 495 F3d 695 (DC Cir 2007).

12. United States v Rutherford, 442 US 544 (1979).

13. Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act of 2017, Pub L No. 115-176, 132 Stat 1372 (2018).

14. US Food and Drug Administration. Regulatory considerations for human drug products containing peptides. Guidance for Industry (draft). 2020.

15. Ruenzi M, Stolte M, Veljaca M, et al. Efficacy and safety of PL 14736 (BPC 157) in patients with active ulcerative colitis [abstract]. Gastroenterology. 2005. Meeting abstract; full study not published.

16. Staresinic M, Petrovic I, Novinscak T, et al. Effective therapy of transected quadriceps muscle in rat: gastric pentadecapeptide BPC 157. J Orthop Res. 2006;24(5):1109-1117. doi:10.1002/jor.20089

17. Gwyer D, Wragg NM, Wilson SL. Gastric pentadecapeptide body protection compound BPC 157 and its role in accelerating musculoskeletal soft tissue healing. Cell Tissue Res. 2019;377(2):153-159. doi:10.1007/s00441-019-03016-8

18. Sikiric P, Skrtic A, Gojkovic S, et al. Stable gastric pentadecapeptide BPC 157 and hemorrhage/thrombosis. Pharmaceuticals (Basel). 2026;19(3):463. doi:10.3390/ph19030463

19. Stavchansky VV, Filippenkov IB, Dergunova LV, Limborska SA. The role of glyprolines in the regulation of gene expression: focus on Semax. Genes (Basel). 2022;13(12):2380. doi:10.3390/genes13122380

20. Mendias CL, Awan TM. The safety and efficacy of approved and unapproved peptides. Sports Med. 2026. doi:10.1007/s40279-026-02437-0

21. Moseley JB, O'Malley K, Petersen NJ, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med. 2002;347(2):81-88. doi:10.1056/NEJMoa013259

22. Cobb LA, Thomas GI, Dillard DH, Merendino KA, Bruce RA. An evaluation of internal-mammary-artery ligation by a double-blind technic. N Engl J Med. 1959;260(22):1115-1118.

23. Dimond EG, Kittle CF, Crockett JE. Comparison of internal mammary artery ligation and sham operation for angina pectoris. Am J Cardiol. 1960;5:483-486.

24. Alfredson H, Pietila T, Jonsson P, Lorentzon R. Heavy-load eccentric calf muscle training for the treatment of chronic Achilles tendinosis. Am J Sports Med. 1998;26(3):360-366. doi:10.1177/03635465980260030301

25. Kongsgaard M, Kovanen V, Aagaard P, et al. Corticosteroid injections, eccentric decline squat training and heavy slow resistance training in patellar tendinopathy. Scand J Med Sci Sports. 2009;19(6):790-802. doi:10.1111/j.1600-0838.2009.00949.x

26. Langberg H, Skovgaard D, Karamouzis M, Bulow J, Kjaer M. Metabolism and inflammatory mediators in the peritendinous space measured by microdialysis during intermittent isometric exercise in humans. J Physiol. 1999;515(Pt 3):919-927. doi:10.1111/j.1469-7793.1999.919ab.x

27. Coombes BK, Bisset L, Brooks P, Khan A, Vicenzino B. Effect of corticosteroid injection, physiotherapy, or both on clinical outcomes in patients with unilateral lateral epicondylalgia: a randomized controlled trial. JAMA. 2013;309(5):461-469. doi:10.1001/jama.2013.129

28. Kearney RS, Ji C, Warwick J, et al. Effect of platelet-rich plasma injection vs sham injection on tendon dysfunction in chronic midportion Achilles tendinopathy: a randomized clinical trial. JAMA. 2021;326(2):137-144. doi:10.1001/jama.2021.6986

29. Pavlova AV, Shim JSC, Moss R, et al. Effect of resistance exercise dose components for tendinopathy management: a systematic review with meta-analysis. Br J Sports Med. 2023;57(20):1327-1334. doi:10.1136/bjsports-2022-105754

30. Weintraub M, Sundaresan PR, Madan M, et al. Long-term weight control study I (weeks 0 to 34): fenfluramine plus phentermine versus placebo. Clin Pharmacol Ther. 1992;51(5):586-594. doi:10.1038/clpt.1992.69

31. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997;337(9):581-588. doi:10.1056/NEJM199708283370901

32. Centers for Disease Control and Prevention. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: interim public health recommendations, 1997. MMWR Morb Mortal Wkly Rep. 1997;46(45):1061-1066.

33. Bombardier C, Laine L, Reicin A, et al; VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000;343(21):1520-1528. doi:10.1056/NEJM200011233432103

34. Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet. 2005;365(9458):475-481. doi:10.1016/S0140-6736(05)17864-7

35. Smith RM, Schaefer MK, Kainer MA, et al; Multistate Fungal Infection Outbreak Response Team. Fungal infections associated with contaminated methylprednisolone injections. N Engl J Med. 2013;369(17):1598-1609. doi:10.1056/NEJMoa1213978

36. Adunsky A, Chandler J, Heyden N, et al. MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: a multicenter, randomized, placebo-controlled phase IIb study. Arch Gerontol Geriatr. 2011;53(2):183-189. doi:10.1016/j.archger.2010.10.004 [Trial terminated early for a congestive-heart-failure safety signal.]

37. Nass R, Pezzoli SS, Oliveri MC, et al. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Ann Intern Med. 2008;149(9):601-611. doi:10.7326/0003-4819-149-9-200811040-00003

38. Van Wagoner RM, Eichner A, Bhasin S, Deuster PA, Eichner D. Chemical composition and labeling of substances marketed as selective androgen receptor modulators and sold via the internet. JAMA. 2017;318(20):2004-2010. doi:10.1001/jama.2017.17069

39. ECRI and Institute for Safe Medication Practices. Unapproved peptide products: safety and quality concerns [white paper]. Plymouth Meeting, PA: ECRI; April 2026.

40. Center for Science in the Public Interest. What are injectable peptides, and are they safe? Accessed July 24, 2026. https://www.cspinet.org

41. World Anti-Doping Agency. The 2026 Prohibited List. Montreal, QC: WADA; 2026. Accessed July 24, 2026. https://www.wada-ama.org

42. US Anti-Doping Agency. BPC-157: a prohibited peptide. Accessed July 24, 2026. https://www.usada.org

43. FDA committee votes in favor of compounding several peptides. Time. July 23, 2026. Accessed July 24, 2026. https://time.com

44. FDA advisory committee backs controversial peptides. Regulatory Affairs Professionals Society (RAPS). 2026. Accessed July 24, 2026. https://www.raps.org

45. FDA panel okays peptides for compounding, including BPC-157 and KPV. STAT News. July 23, 2026. Accessed July 24, 2026. https://www.statnews.com

46. FDA panel recommends easing peptide restrictions over agency scientists' objections. NBC News. 2026. Accessed July 24, 2026. https://www.nbcnews.com

47. Associated Press. Financial ties reported among FDA peptide advisory panel members. 2026. Accessed July 24, 2026.

48. Leerink Partners. Equity research note: PCAC peptide vote and the telehealth compounding market. 2026.

49. Examine.com. BPC-157 research breakdown. Accessed July 24, 2026. https://examine.com/supplements/bpc-157/

50. Jarry J. Body protection compound: no proof required. McGill Office for Science and Society. Accessed July 24, 2026. https://www.mcgill.ca/oss

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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.

Timestamps

• 00:00:00 Cold open: the man who couldn’t stop gaining weight
• 00:01:49 Meet the case (and the rules of the game)
• 00:02:36 The presentation: 21, headaches, unexplained weight gain
• 00:03:57 Austin’s one-liner and how a clinician builds a differential
• 00:05:10 Secondary headaches: what raises the red flag
• 00:13:12 The exam: vitals, and the eye findings that matter
• 00:14:37 The labs, one number at a time
• 00:16:08 Raised pressure and a visual-field clue (bitemporal hemianopia)
• 00:20:45 The MRI
• 00:21:54 First diagnosis: craniopharyngioma
• 00:25:32 The name: a tumor built from tooth tissue
• 00:25:50 Surgery, and what it costs
• 00:27:43 The new mystery: gaining weight faster than ever
• 00:33:41 Second diagnosis: acquired hypothalamic obesity
• 00:39:17 How your brain sets your weight: the POMC brake and the AgRP accelerator
• 00:42:07 What about leptin?
• 00:45:46 Monogenic vs common obesity
• 00:50:30 Why GLP-1 drugs still worked: the brainstem backdoor
• 00:52:11 Responders and non-responders
• 00:55:40 Setmelanotide: a drug for the broken circuit
• 00:56:53 TRANSCEND, and the new FDA approval
• 00:58:55 What it costs
• 01:01:32 Why we care about body fat at all: the garage
• 01:04:36 Flux: which fat is actually dangerous
• 01:09:15 Close

Resources

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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. 

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