Evaluating the Influence of Diet-induced Weight Loss on Fat (Adipose) Tissue's Insulin Sensitivity and Testosterone Synthesis in Women With Overweight or Obesity, Insulin Resistance, and Hyperandrogenemia

The investigators will measure the efficacy of a diet-induced weight loss intervention to reduce blood concentrations of the hormone's insulin and testosterone over the course of 2 months in women who have overweight or obesity and evidence of IR. Women meeting the eligibility criteria that have biochemical evidence or clinical manifestations of hyperandrogenemia (HA), or elevated blood androgens - testosterone or free testosterone - will be eligible for the dietary intervention arm of the study. A Mediterranean-based, calorie reduced, carbohydrate restricted diet will be employed to produce a 5% weight loss over the 8 weeks of the intervention. Participants will be provided with a full menu of meals and snacks for 4 of the 8 weeks in the study and will meet with a registered, licensed dietitian routinely for nutrition counseling and to ensure dietary compliance. Those in the dietary intervention will undergo 6 clinical visits at the Clinical and Translational Science's Unit whereas the control group (no dietary intervention or nutrition counseling) will undergo 2 clinical visits. Of the 6 study visits, 4 will include an adipose tissue biopsy and an oral glucose tolerance test. All visits will include DEXA measurement of body composition and collection of fasting blood samples. The control group's 2 study visits will occur at the start and end of the 8-week period and will include all study measurements (i.e., adipose tissue biopsies, oral glucose tolerance tests, DEXA scans, and fasting blood samples). Adipose tissue samples will be cultured and used to assess adipose-level insulin sensitivity. Area under the curve for insulin, glucose, and non-esterified fatty acids (NEFA) will be calculated from the samples collected during the oral glucose tolerance test. Additionally, the fasting HOMA-IR, Matsuda Index, QUICKI value, 2-hour blood glucose concentration, and NEFA suppression will be measured during the oral glucose tolerance test.

Inclusion criteria

• Women (female sex, premenopausal)
• Age 21-45y
• Overweight/obesity with BMI ≥25.0 or ≤50.0 kg/m2
• Prediabetic (fasting glucose between 100-125 mg/dL,HbA1c between 5.7-6.4%, blood glucose ≥ 140 mg/dL, but ≤ 200 mg/dL at 2 hours into OGTT) or diabetic with a fasting glucose <200 mg/dL, stably treated with metformin for 2 months or longer
• Alternatively: if not prediabetic as evidenced by abnormal fasting blood glucose or glucose tolerance, evidence of insulin resistance such as fasting insulin value ≥ 10 µU/mL, elevated HOMA-IR or elevated QUICKI may be substituted

o Prediabetes and diabetes are associated with insulin resistance and excess body weight. Our study seeks to improve impaired insulin signaling through weight loss from dietary restriction. Therefore, insulin resistance in the presence of normal glucose tolerance may still be improved through this intervention.

• Plasma testosterone concentration <200 ng/dL, as measured at screening visit
• Weight stable: No fluctuations in body weight of greater than 4 kg in the last 2 months (see exclusion criteria for undergoing weight loss)
• Presence of central (android) obesity as defined by WHR > 0.8 or waist circumference > 80 cm
• No use or active use of hormonal contraceptives (IUD, oral contraceptive pill, Nexplanon)

o Hormonal contraceptives are not expected to alter the outcomes of this study; therefore, their use is not prohibited. However, it is not a requirement that women use hormonal contraception to be part of this study.

• Willingness to consume a defined diet (Intervention arm - Weight loss)

Exclusion criteria

• Pregnant or trying to become pregnant
• Postmenopausal as testosterone naturally increases with menopause
• BMI of <25.0 or >50.0 kg/m2
• Use of tobacco, cannabis, or other recreational drug products.

o Tobacco and other recreational drugs products are excluded as they known to increase adipose lipolysis. Cannabis products are excluded as they are fat soluble compounds and could alter the adipose gene and protein expression.

• Taking medications known to affect adipose tissue metabolism (steroids, niacin)
• Use of antiandrogen medications (spironolactone, flutamide, finasteride) within the last 3 months o These medications are designed to lower testosterone concentrations.
• Already undergoing weight loss. o As this study is investigating the impact of weight loss, the goal is to obtain samples before and after weight loss (intervention arm) or during weight stability (control arm).
• Diagnosis of congenital adrenal hyperplasia, or Cushing syndrome o These conditions are associated with significantly high androgens in need of medical treatment.