Exercise is Medicine: Translational Research in Obesity and Insulin Resistance Alice S. Ryan, Ph.D. Baltimore VA Medical Center University of MD School of Medicine

“basic muscle- strengthening activities twice a week … and find two and a half more hours in your week for moderate aerobic activity.” – Science of Healthy Living Advice from Newsweek 2010

Percentage of Adults Who Reported No Leisure-Time Physical Activity by Age in Maryland,

Data from CDC National Center for Chronic Disease Prevention & Health Promotion Behavioral Risk Factor Surveillance System % BMI>3028% % BMI>25 40% 31% 12%

BMI (kg/m 2 ) < >35 < >35 Percent Diabetic Age (years) Prevalence of Diabetes by Age and Obesity

Abdominal Fat Mid-thigh is the Fat? Where is the Fat?

Visceral and Subcutaneous Adipose Depots Fat Distribution Trends in Postmenopausal Women Sample: Caucasian N = 50 – 80 per group Total and Central Obesity

Increased Fasting Glucose & Insulin across VAT quintiles VAT quintiles (cm 2 ) 11 1,2, 3 1 Numbers signify P<0.05 from quintiles 1, 2, 3 Analyses adjusted for age, fat mass, & race 1 1,2,3 Nicklas et al. Diabetes Care, 2003

VAT of ~ cm 2 is predictive of adverse lipid (HDL, TG) and diabetes risk factors in women.  Depres and Lamarche, Nutr Res Rev, 1993  Williams MJ et al, Int J Obes Relat Metab Disord, 1996  Nicklas et al., Diabetes Care, 2003 Visceral Adipose Tissue Risk

Exercise Reduces Visceral Fat in Women Athletes N = 10 – 14 per group Ryan et al. Am J of Physiol, 1996    P < 0.01 VAT (cm 2 )

Visceral Adipose Tissue Decreases with ↑VO 2 max r=-0.47, p<0.01 Lynch et al., J Appl Physiol, 2001

Insulin 80mU/min BEDSIDE Measurement of Insulin Sensitivity: Hyperinsulinemic-euglycemic clamp

Chronic Exercise in Older Women Prevents the Decline in Insulin Sensitivity Observed with Aging Ryan et al. J Appl Physiol, 2001 Glucose Uptake (umol/kg FFM /min ) (umol/kg FFM /min ) *P < ControlsAthletes *

Older Elite Football Players have Reduced Cardiac Risk Factors Former Colts compared to age, BMI, race and current physical activity level matched men:  26% lower visceral fat and lower total body fat (p<0.01).  13% higher muscle mass (p<0.01)  37% higher HDL-C & 31% lower TG (p<0.05) Suggests that the high levels of exercise in young adulthood conferred benefits later in life Lynch et al. Med Sci Sports Exerc, 2007

Can We Modify Obesity and Insulin Resistance with Exercise Training?

Dietary Stabilization 0 m 6 m 12 m Study Design Interventions WL: 1x/wk AEX+WL: 3x/wk Weight Stable 2 wks Metabolic Testing Screening Enrollment year old Caucasian or African American women Postmenopausal (1 year) BMI: 25 – 50 kg/m2 Sedentary, Weight stable Non-smokers (≥ 1 year) No symptomatic heart disease or medications interfering with muscle metabolism

0 m 6 m 12 m Study Design Interventions Metabolic Testing VO 2 max, Body Composition (DXA, CT) 3-hr OGTT 3 hr 80 mU/m 2 /min Hyperinsulinemic- euglycemic Clamp w/Indirect Calorimetry Skeletal Muscle Biopsy (basal Gluteal & Abdominal Adipose Tissue Biopsy Metabolic Testing

Study Design Screening N ~ 3000 Enrollment N = 292 AEX+WL N = 88 Entered WL N = 86 Entered Metabolic Testing N = 174 AEX+WL N = 53 Completed WL N = 50 Completed Dropped N = 63 Completed & Noncompliant N=8

WeightVO 2 max * * * (kg) (l/min) Successful Weight Loss with AEX+WL and WL Improvements in Fitness only with AEX+WL *P<0.001  14%  8% ‡P<0.05 AEX+WL vs. WL ‡

Fat MassFFM (kg) Losses of both Fat Mass and FFM with AEX+WL and WL  16%  13% * *  2%  4% * P<0.001 ‡P<0.05 ‡ ‡

Visceral Fat Area Mid-thigh Intramyocellular Lipid Reductions in Abdominal and Intra-muscular Fat (cm 2 )  16%  13%  9% *P<0.001 * * + +

Improvements in Insulin Sensitivity Glucose Uptake (  mol/kg FFM /min)  14%  6% * * P<0.01 ‡P<0.05

Improvements in Insulin Sensitivity are associated with an Increase in Fitness ∆ VO 2 max (l/min) ∆ M (µmol/kg FFM /min) r=0.30,P<0.05

Mechanisms of Action of Lifestyle Interventions Muscle Adipose  Insulin Sensitivity  Capillarization  Insulin Activation of Glycogen Synthase ↑ Enzymes of Fatty Acid Metabolism  Inflammation  Fat stores Exercise Training Weight Loss

“BEDSIDE TO BENCH” Skeletal Muscle and Adipose Tissue of Exercise Mechanisms of Exercise Gluteal Adipose Tissue BiopsyVastus Lateralis Biopsy

Skeletal Muscle Capillarization and Fiber Type Double Stain Myosin ATPase CD: Capillary Density (cap/mm 2 ) CFPE: Capillary-to-fiber perimeter exchange index (cap/mm perimeter) Type I: stain dark brown/black Type IIa: stain light brown/white Type IIx: stain brown

VASCULAR and SYSTEMIC MARKERS in NGT (n = 42) and IGT (n = 28) Postmenopausal Women * a P =0.06, * P<0.01, † P<0.005 IGT women were older, had a higher BMI, and a lower M than NGT. † a VASCULAR and SYSTEMIC MARKERS in NGT (n = 42) and IGT (n = 28) Postmenopausal Women * a P =0.06, * P<0.01, † P<0.005 IGT women were older, had a higher BMI, and a lower M than NGT. † a VASCULAR and SYSTEMIC MARKERS in NGT (n = 42) and IGT (n = 28) Postmenopausal Women * a P =0.06, * P<0.01, † P<0.005 IGT women were older, had a higher BMI, and a lower M than NGT. † a Reduced Skeletal Muscle Capillarization is Associated with Glucose Intolerance Prior et al. Microcirculation, 2009

Insulin Sensitivity is Reduced In Women with Impaired Glucose Tolerance Glucose Uptake (  mol/kg FFM /min) * * P<0.01 n = 64 n = 34

FastingInsulin-Stimulated MetabolicInflexibility inObeseSubjects lean obese Kelly & Mandarino, Diabetes 2000 Metabolic Inflexibility  Ability to switch from fat utilization during fasting to carbohydrate utilization during hyperinsulinemia (Kelley et al. 2000)  Clamp RQ – Fasting RQ

Metabolic Flexibility is Associated with Insulin Sensitivity in Postmenopausal Women n = 92, r=0.46, P<0.0001

 =-3%, P=NS  =49%, P<0.05 P<0.01 Exercise + Weight Loss Increases Muscle LPL WL AEX+WL Pre Post Skeletal Muscle Lipoprotein Lipase

Pre Post  =-6%, P=NS  =45%, P<0.05 P<0.05 Muscle Acyl-CoA Synthase Exercise + Weight Loss Increases Skeletal Muscle ACS

 =-1%, p=NS  =32%, P=0.05 P<0.08 Muscle Citrate Synthase Pre Post Exercise + Weight Loss Increases Skeletal Muscle CS

 =-18%, P=0.01  =-26%, P<0.001  =-14%, P=NS  =-28%, P<0.001 Exercise + Weight Loss Decreases Adipose Tissue LPL Gluteal Lipoprotein LipaseAbdominal Lipoprotein Lipase Pre Post

 =54%, p=NS  =-32%, P=0.005 P<0.05 Exercise + Weight Loss Shifts Lipid Partitioning from Storage to Oxidation Ratio of Abdominal to SM-LPL Pre Post Ratio of Gluteal to SM-LPL  =-24%, p<0.05 Pre Post P<0.09

Insulin Suppresses ACS after Exercise Training Change in insulin’s effect on ACS after AEX+WL in postmenopausal women (n = 17, *P<0.05). *

Insulin Suppresses  -HAD after Exercise Training Change in insulin’s effect on  -HAD after AEX+WL in postmenopausal women (n = 17, *P<0.05). *

“Bench to Bedside” How is this Translated to an Exercise Prescription?

Summary of the ACSM/AHA Updated Physical Activity Guidelines for Healthy Adults Under Age 65 Do moderate-intensity cardiovascular activity for 30 minutes a day, 5 days a week or Do vigorous cardiovascular activity 20 minutes a day, 3 days a week and Do 8 – 10 resistance-training exercises, performing 8 – 12 repetitions for each exercise, twice a week Moderate-intensity physical activity means working hard enough to raise your heart rate and break a sweat, yet still being able to carry on a conversation. It should be noted that to lose weight or maintain weight loss, 60 to 90 minutes of physical activity may be necessary. The 30- minute recommendation is for the average healthy adult to maintain health and reduce the risk for chronic disease. Med Sci Sports Exercise: 39(8); , 2007

Benefits of Aerobic Exercise Improved cardio-respiratory fitness Weight Control Improved Endurance Stress Relief Improved energy Decreased fatigue Improved immune system Improved quality of sleep Psychological benefits

Physical Activity Pyramid Leisure Time Activity Cardiovascular Exercise Strength TrainingFlexibility Inactivity in moderation

Acknowledgements Many Thanks! Investigators: Andrew Goldberg, M.D. Heidi Ortmeyer, Ph.D. Jacob Blumenthal, M.D. Lyndon Joseph, Ph.D. Susan Fried, Ph.D. John McLenithan, Ph.D. Steve Prior, Ph.D. Clinical Staff: Joyce Evans, R.N. Sarah Witten, R.N. Kathie Brandt, R.N. Ivey Dorsey, R.N. Anita Neal, L.P.N. Cheryl Beasley, L.P.N. Luz Ortiz-Corral, R.N. Lynn Stars-Zorn, N.P. Linda Hatler, N.P. Peter Normandt, N.P. Dieticians: Kelly Ort, R.D. Kathy Simpson, R.D. Andriane Kozlovsky, R.D Amy Matson, R.D. Tara Caulder, R.D. Exercise Physiologists: Lynda Robey, M.S. Gretchen Zietowski, M.S., R.N. Greig Frietag, M.S. Nicole Fendrick, M.S.. Melinda Erbe, M.S. Research Assistants: Melissa Gray Keisha Galloway, M.S. Agnes Kohler, M.S. Carole St. Clair Sara Herts Jonelle George Linsday Koepper Urmila Sreenivasan Tara McDonald Lisa McFarland Sumi Khan Nikki Glynn Funding: VA NIH