Exercise and Prolonged Fasting to Improve Brown Adipose Tissue Function in Postmenopausal Women

Overview

Type of Study: Clinical Trial Goal: The goal of this clinical trial is to investigate mitochondrial function in interscapular brown adipose tissue (iBAT) in postmenopausal women and determine whether aerobic exercise, prolonged fasting, or their combination can improve iBAT mitochondrial function and whole-body metabolic flexibility. Participant Population/Health Conditions: The study will involve 60 postmenopausal women aged 45-65 years living with overweight or obesity. Main Questions: The main questions this study aims to answer are: * What are the mitochondrial function and cellular characteristics of iBAT in postmenopausal women? * Can aerobic exercise or five-day prolonged fasting improve mitochondrial function in iBAT and whole-body metabolic flexibility? * Does combining aerobic exercise with prolonged fasting produce greater metabolic adaptations than either intervention alone? * Are improvements in metabolic flexibility maintained four weeks after the intervention? Participants Will: Be randomized into one of four groups: control, aerobic exercise, prolonged fasting, or combined aerobic exercise plus prolonged fasting. Follow their assigned intervention for five consecutive days. Undergo metabolic and physiological assessments before and after the intervention and again four weeks later. Provide dorsocervical adipose tissue biopsies and biological samples to investigate mitochondrial function, adipocyte characteristics, and metabolic adaptations. Comparison Group: Researchers will compare the effects of aerobic exercise, prolonged fasting, and their combination with a control condition to determine their effects on iBAT mitochondrial function and whole-body metabolic flexibility.

Postmenopause is associated with a substantial increase in cardiometabolic risk, partly driven by the decline in estrogen levels and alterations in cellular energy metabolism. Mitochondrial dysfunction has been documented in skeletal muscle of postmenopausal women and is associated with metabolic inflexibility, reduced fat oxidation, ectopic fat accumulation, and insulin resistance. However, whether mitochondrial dysfunction is also present in adipose tissue of postmenopausal women, and whether it can be reversed through lifestyle interventions, remains largely unknown. Brown adipose tissue (BAT) is a mitochondria-rich and metabolically active tissue involved in thermogenesis and substrate utilization. Although human BAT has traditionally been studied in the supraclavicular region, emerging evidence from our research group suggests the presence of a metabolically active adipose tissue depot in the dorsocervical region, referred to as interscapular brown adipose tissue (iBAT). Preliminary observations indicate that this depot may have distinct metabolic characteristics. However, iBAT has not yet been characterized in postmenopausal women. Aerobic exercise is a potent non-pharmacological stimulus for mitochondrial remodeling and improves mitochondrial biogenesis and oxidative capacity. Exercise-derived lactate may also promote adipose tissue browning and mitochondrial remodeling. Prolonged fasting induces profound metabolic adaptations characterized by increased fat mobilization and changes in substrate utilization. Preliminary data from our group suggest that five days of prolonged fasting substantially increase fat oxidation during exercise, providing a rationale for investigating whether fasting and exercise may have complementary effects on mitochondrial function and metabolic flexibility. Based on this rationale, the main hypothesis of EMPOWER-BAT is that iBAT in postmenopausal women presents mitochondrial dysfunction and that aerobic exercise, five-day prolonged fasting, and their combination can improve mitochondrial function through lactate-related signaling pathways, leading to enhanced whole-body metabolic flexibility. The main objective is to characterize mitochondrial function in iBAT and determine the effects of these interventions on iBAT mitochondrial function and metabolic flexibility. EMPOWER-BAT is a randomized controlled trial involving 60 postmenopausal women aged 45-65 years with a body mass index ≥25 kg/m². Participants will be randomized (1:1:1:1) into four groups: a control group maintaining its usual lifestyle; an aerobic exercise group performing supervised exercise for 60-90 minutes at 65% of heart rate reserve; a prolonged fasting group following a medically supervised fasting protocol providing approximately 600 kcal/day; or a combined group completing both exercise and fasting. All interventions will last five consecutive days. Before and after the intervention, iBAT biopsies will be collected from the dorsocervical region to assess mitochondrial function and adipocyte characteristics. Metabolic and physiological assessments will include indirect calorimetry at rest and during exercise, body composition, cardiorespiratory fitness, and blood and urine biomarkers. Continuous glucose and ketone monitoring will also be performed during the intervention. Four weeks later, metabolic and physiological assessments will be repeated to determine whether changes in metabolic flexibility are maintained after participants return to their usual lifestyle.