Effect of Time-restricted Eating on Catecholamine-sensitivity of Adipose Tissue in Obese Adults

The current worldwide epidemic of obesity puts millions of people at increased risk for cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM), and while insulin resistance has been a traditional focus of treatment, resistance to catecholamines in obesity is likely a key factor hampering weight loss efforts. Catecholamines are key drivers of lipolysis in adipose tissue and bind to beta-3 adrenergic receptors (ADRB3) on the surface of adipocytes. Chronic inflammation is characteristic of obesity and suppresses the expression of adipocyte ADRB3, increasing fat storage. This leaves adipose tissue metabolically inflexible and in a state of energy preservation instead of burning fat to promote and maintain weight loss. Thus, catecholamine resistance of adipose tissue is an important target for lifestyle and therapeutic intervention. Time-restricted eating (TRE) is a therapeutic intervention that promotes weight loss and healthier metabolism by aligning dietary intake with circadian rhythms. In this RCT, individuals with obesity will be enrolled in a 14-week study of TRE and behavioral nutritional counseling vs behavioral nutritional counseling alone. In the TRE group, dietary intake will be limited to a self-selected 10-hour window. Information will be collected about adipose tissue catabolism (lipolysis) using samples collected by adipose tissue biopsy of subcutaneous abdominal adipose tissue.

Inclusion criteria

• Age: ≥ 18 years old
• BMI 30-50 kg/m2
• Own a smartphone with Apple iOS or Android OS
• Baseline eating window ≥ 14 hours/day
• If patients are on cardiovascular medications (HMG CoA reductase inhibitors (statins), other lipid modifying drugs (including over the counter drugs such as red yeast rice and fish oil), anti-hypertensive drugs, no dose adjustments will be allowed during the study period.

Exclusion criteria

• Taking insulin or anti-diabetic medications within the last 6 months.
• Manifest diabetes, defined as fasting glucose ≥ 126 mg/dL, HbA1c ≥ 6.5%, or diagnosis of diabetes.
• Currently taking any medication that is meant for, or has known effect on, appetite or body weight
• Pregnant or breast-feeding women.
• Caregiver for a dependent requiring frequent nocturnal care/sleep interruptions. Shift workers with variable (e.g. nocturnal) hours.
• Planned international travel (time zone changes) during study period.
• Taking therapeutic anticoagulation which might increase risk of bleeding from adipose tissue biopsy
• History of surgical intervention for weight loss.
• History of eating disorder
• Currently enrolled in a weight-loss or weight-management program
• On a special or prescribed diet for other reasons (e.g. Celiac disease)
• Known inflammatory and/or rheumatologic disease
• Active tobacco abuse or illicit drug use or history of treatment for alcohol abuse
• History of bone marrow or solid organ transplant
• History of heart failure
• History of major adverse cardiovascular events (acute coronary syndrome (ACS), percutaneous coronary intervention, coronary artery bypass graft surgery, stroke/transient ischemic attack (TIA)).
• History of atrial fibrillation or atrial flutter
• History of malignancy, other than non-melanoma skin cancer, that is currently being treated, or that has not been treated with definitive therapy and considered to be in remission.
• History of hypo- or hyperthyroidism requiring dose titration of thyroid replacement medication(s) within the past 3 months (i.e. hypothyroidism on a stable dose of thyroid replacement therapy is not an exclusion)
• History of adrenal disease
• History of cirrhosis
• History of stage 4 or 5 chronic kidney disease or requiring dialysis
• History of HIV/AIDS
• Uncontrolled psychiatric disorder (including history of hospitalization for psychiatric illness).
• History of obstructive sleep apnea (not on stable positive pressure therapy or other treatment for at least 3 months prior to enrollment)
• Abnormal screening labs: renal dysfunction (eGFR < 30 ml/min/1.73 m2), anemia, hypo- or hyperthyroidism, coagulopathy, abnormal liver function (AST, ALT > 3x upper limit of normal)