Metabolic Flexibility and Metabolic Heath in Human Obesity

Obesity is a well-established risk factor for disruptions in metabolic health, which often precede cardiovascular disease and type-2 diabetes. While the precise pathophysiological mechanisms linking obesity to these conditions remain unclear, it is widely acknowledged that an increase in fat mass plays a central role, including the expansion of adipose tissue and the accumulation of lipids in non-adipose tissues. As a result, a primary approach to improving metabolic health is to reduce fat mass through negative energy balance. However, lifestyle changes or pharmacological interventions aimed at inducing a negative energy balance do not exclusively target fat mass and often result in the loss of fat-free mass to varying degrees. Given that higher fat mass, rather than fat-free mass, is more strongly associated with impaired metabolic health, strategies that maximize fat mass loss while preserving fat-free mass may offer more significant benefits for metabolic health. Surprisingly, there is a lack of evidence to support this hypothesis. To address this gap, it will be evaluated the relationship between changes in metabolic health and body composition, independent of overall weight loss, in individuals with overweight or obesity undergoing dietary energy restriction. It is hypothesized that greater fat mass reduction will be linked to more substantial improvements in metabolic health for a given weight loss.

Inclusion criteria

• males or females
• 30-55 y old
• physically inactive (<600 MET´min/wk of self-reported moderate-vigorous physical activity
• stable body weight for at least the past 6 months (±2 kg)
• healthy according to medical history and routine hematology and biochemistry.

Exclusion criteria

• Individuals with physiological (pregnancy, lactation) or pathological (under drug therapy for and/or having cardiovascular, liver, kidney, thyroid diseases)
• conditions affecting energy metabolism or eating behavior
• Subjects having low-fat (<20% energy) or low-carbohydrate (<45% energy) diets
• Smokers and alcohol abusers