The Physiological Responses and Adaptation of Brown Adipose Tissue to Chronic Treatment With Beta3-Adrenergic Receptor Agonists

Inclusion criteria

• In order to be eligible to participate in this study, an individual must meet all of the following criteria: Cohort 1: (complete)
• Age 18-40 years
• BMI 18.00-40.0 kg/m\^2
• Able to understand the research and willing to sign a written informed consent document Cohort 2: (complete)
• Age 18-40 years
• BMI 18.00-40.0 kg/m\^2
• Able to understand the research and willing to sign a written informed consent document Cohort 3:
• Age 18-40 years
• BMI 25.0-50.0 kg/m\^2 or BMI \> 18.5 kg/m\^2 with PCOS diagnosis
• Diagnosis of PCOS based on NIH Criteria; defined by the presence of both clinical and/or biochemical signs of hyperandrogenism and oligo- or chronic anovulation.
• Women of childbearing potential must agree to use a highly effective method of birth control, confirmed by the Investigator, for at least 3 months prior to the first study visit and continuing throughout the study duration. a. Highly effective methods of birth control include: i. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal ii. Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable iii. Intrauterine device iv. Intrauterine hormone-releasing system v. Bilateral tubal occlusion vi. Sexual abstinence, i.e., refraining from heterosexual intercourse (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant) vii. Vasectomized sexual partner (provided that partner is the sole sexual partner of the study participant and that the vasectomized partner has received medical assessment of the surgical success) b. Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for \>=12 months prior to the planned date of enrollment without an alternative medical cause.
• Insulin resistance defined by either
• HOMA-IR score \> 5.9 OR
• HOMA-IR score \> 2.8 and \<5.9, with HDL \<51 mg/dL OR
• Fasting Insulin \> 10.6 microU/mL
• Able to understand the research and willing to sign a written informed consent document

Exclusion criteria

• Hypersensitivity and associated allergic reactions to mirabegron (or similar drug substances or components)
• Abnormal bladder function, diagnosis of bladder outlet obstruction, urinary incontinence, urgency, and urinary frequency or use of antimuscarinic medication to treat overactive bladder (OAB)
• Type 1 or Type 2 Diabetes mellitus, fasting serum glucose \>125 mg/dL, and/or an HbA1c test \>6.5%
• Hypertension, defined as blood pressure (Bullet)140/90 mmHg, based on WHO guidelines (https://www.who.int/news-room/fact-sheets/detail/hypertension)
• Hypo- or hyper-thyroid disease (TSH \>5.0, \<0.4 miU/L) that is controlled for less than one year
• Anemia, defined by hemoglobin \< 11.3 g/dL (females) or \< 13.8 g/dL (males); sickle cell anemia or other blood disorders; and/or wound healing problems
• Cardiovascular disease, cardiac arrhythmias, orthostasis, unstable vasomotor system, or renal impairment
• A clinically significant abnormal ECG and/or QTc interval above normal
• Elevated liver enzymes with probable or diagnosed liver disease (other than fatty liver disease)
• Psychological conditions such as claustrophobia, untreated clinical depression or anxiety, untreated bipolar disorders, or forms of mental incapacity that would be incompatible with safe and successful participation in this study
• Recent history in last 4 weeks of any local or systemic infectious disease with fever or requiring antibiotics
• Self-reported intolerance of cold that would prevent the individual from spending several hours in a chilled room with a cooling vest
• Current use of any drugs known to:
• have major drug-drug interactions with mirabegron
• Prolong QT interval
• Alter glucose metabolism or cause insulin resistance (in last six months)
• Treat diabetes mellitus
• Treat hypertension
• Be drugs of abuse
• Self-reported weight loss or weight gain \> 5% in the preceding 6 months.
• Pregnancy, childbirth within the last year, or breastfeeding in the past 12 months
• Individuals who spend \>70% of daily hours outdoors since the exposure to varied environmental temperatures will potentially impact the ability to influence and measure BAT activity.
• Addiction to alcohol or substances of abuse within the last 5 years
• Self-reported current alcohol consumption of more than 2 servings of alcohol per day
• Self-reported current use of nicotine and/or tobacco products
• Has participated in a clinical trial with an investigational or marketed drug within 2 months
• Have had previous radiation exposure (X-rays, PET scans, etc.) within the last year or anticipate radiation exposure in the upcoming year - clinical and/or research - that would exceed research limits
• Donated blood within last 2 months
• Unwilling or unable to eat metabolic meals, as determined by dietitian consult.
• Any other circumstances or criteria that would preclude safe participation in the study in the clinical judgment of the investigator