Inclusion Criteria:
* All Groups
1. 30 to 65 years of age
2. Stable weight (No Gain/Loss of \>10 lbs in 6 months)
3. Sedentary (≤ 1 continuous exercise/week)
4. Non-smoker
5. Resting Blood Pressure ≤ 150mmHg systolic and ≤ 95 mmHg diastolic
Group A - Lean individuals with insulin sensitivity (IS-Lean)
1. BMI 18-25 kg/m2
2. Hemoglobin A1c ≤ 5.6% at screening
3. Blood glucose level ≤ 140 mg/dL 2hr after a 75g oral glucose tolerance test
Group B - Individuals with obesity and insulin sensitivity (IS-Obesity)
1. BMI 30-40 kg/m2
2. Hemoglobin A1c ≤ 5.6% at screening
3. Blood glucose level ≤ 140 mg/dL 2hr after a 75g oral glucose tolerance test
Group C - Individuals with obesity and insulin resistance (IR-Obesity)
1. BMI 30-40 kg/m2
2. Hemoglobin A1c ≤ 6.4 % at screening
3. Blood glucose level 140-199 mg/dL 2hr after a 75g oral glucose tolerance test
Exclusion Criteria:
1. Clinically significant CVD including h/o MI, within the past year
2. Peripheral Vascular Disease
3. Diagnosed with Type I or Type II diabetes
4. Hepatic, renal, muscular/neuromuscular, or active hematologic/oncologic disease
5. Previous history of pulmonary emboli
6. Peripheral Neuropathy
7. Anemia (Hematocrit \<34%, Hemoglobin \< 14 gm/dL for men and \<12.3 gm/dL for women) at screening
8. Currently pregnant (pregnancy test performed on day of DEXA scan in women of child-bearing potential); post-partum during the last 12 months; lactating during the last 12 months; planning to become pregnant during the participation period
9. Polycystic Ovarian Syndrome (PCOS) (self-report)
10. Hospitalization for COVID-19 infection in the past 12 months; individuals who tested positive for COVID-19 but were not hospitalized must be symptom-free at least 14 days
11. Partial and/or full hysterectomy (self-report)
12. Not willing to archive biospecimens for future use
13. Any contraindications to exercise testing according to ACSM guidelines
14. Inability and/ or unwillingness to comply with the protocol as written
15. Active alcohol or substance abuse (Past 5 Years)
16. Positive toxicology result from screening visit or chronic use of Amphetamine, Barbiturate, Benzodiazepine, Cocaine, Methadone, Opiate, THC, Cannabis, Tricyclics, or Oxycodone.
17. Dyslipidemia (fasting triglycerides \>500 mg/dL; low-density lipoprotein cholesterol (LDL-C) \>190 mg/dL; total cholesterol \>300 mg/dL);
18. ALT \>80, AST\>80, Alk Phos \>240 if a participant presents with liver functions out of these ranges at screening the MI or PI can give discretion to participate
19. Proteinuria (defined as \> 1+) at screening
20. Kidney disease (creatinine \>1.6 mg/dl or estimated glomerular filtration rate \<60 mL/min/1.73m2);
21. Self-reported chronic, active, or latent infection requiring chronic antibiotic or anti-viral treatment; Human Immunodeficiency Virus (HIV); active hepatitis B or C undergoing antiviral therapy.
22. Receiving active treatment (including monoclonal antibodies) for autoimmune disorders within the last 6 months;
23. Hypothyroidism (sTSH\>8) at screening or on thyroid replacement therapy
24. Abnormal bleeding or coagulopathy (self-report) or history of a bleeding disorder or clotting abnormality
25. History of cancer (other than non-melanoma skin cancer) within the last 5 years (not in remission); anti-hormonal therapy (e.g., for breast or prostate cancer) within the last 6 months;
26. Previous bariatric or other surgery for obesity
27. Females currently on hormone replacement therapy (HRT) less than 6 months
28. Females with an irregular menstrual cycle
29. Previous difficulty with lidocaine or other local anesthetic
30. ACS symptoms:
* Positive ECG (\> 2mm ST segment depression) without PCP cardiologist permission to participate
* Signs or symptoms of cardiovascular decomposition (eg. hypotensive response to exercise)
* Onset of angina or angina like symptoms, shortness of breath, change in heart rhythm, signs of poor perfusion (light-headedness), tightness.
31. The following medication use is exclusionary;
* Dose change for any chronic-use drug in the last 3 months;
* Any medications that can alter glucose homeostasis (eg. steroids, glucocorticoids, nicotinic acid). Acute therapy (5-7 days) is not exclusionary however; participant must be agreeable to a washout period of 5-7 days prior to day of biopsy.
* Blood thinners such as Coumadin, Lovenox etc. Aspirin is not exclusionary however; participant must be agreeable to a washout period of \> 10 days prior to day of biopsy
* All Weight loss medications including but not limited toGLP-1 agonists- Wegovy, liraglutide, semaglutide, Trulicity (dulaglutide), Phentermine and Contrave
* Cardiovascular: beta blockers and centrally acting anti-hypertensive drugs, anticoagulants, antiarrhythmics, and antiplatelet drugs (other than aspirin ≤100 mg/day);
* Psychiatric: chronic use of medium- or long-acting sedatives and hypnotics, including all benzodiazepines (short-acting non-benzodiazepine sedative-hypnotics are allowed), mood stabilizers, antiepileptic drugs, stimulants, Attention-Deficit/Hyperactivity Disorder (ADHD) drugs, anti-psychotic drugs, anti-depressant medication (e.g. Bupropion, selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine re-uptake inhibitors (SNRIs)).
* Pulmonary/Inflammation: chronic oral steroids (occasional use of inhaled steroids are allowed), burst/taper oral steroids more than once in the last 12 months, B2-agonists (allowed if on stable dose at least 3 months).
* Genitourinary: 5-alpha reductase inhibitors, daily use of phosphodiesterase type 5 inhibitor.
* Hormonal: androgenic anabolic steroids, anti-estrogens, anti-androgens, estrogens and/or progestins used for reasons other than birth control, growth hormone, insulin like growth factor-I, growth hormone releasing hormone,
* any drugs used to treat diabetes mellitus or lower blood glucose including metformin, thiazolidinediones, SGLT-2 inhibits or insulin
* any drugs used specifically to induce muscle growth/hypertrophy or augment exercise-induced muscle hypertrophy
* Pain/Inflammation: narcotics and narcotic receptor agonists, regular use of non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen, muscle relaxants ≥2 days per week
* Other: chronic systemic antimicrobials (antibiotic, antiviral, antifungal, antiparasite, etc.) for any reason, high-potency topical steroids if ≥10% surface area using rule of 9s, continuous/chronic use of antibiotics or other anti-infectives for treatment or prevention, monoclonal antibodies, anti-rejection medications/immune suppressants. Participants can be re-screened after a 3 month washout period if antimicrobial use is only used acutely \< 2 weeks.
32. Presence of any condition that, in the opinion of the Investigator, compromises participant safety or data integrity or the participant's ability to complete the study.
