Why It’s Hard to Lose Weight
Leptin plays a crucial role in regulating body weight and energy balance. It acts as a signal of adipose tissue stores and influences the body's response to weight loss efforts. This article discusses leptin beyond its role in signaling adipose tissue size by exploring the prenatal, perinatal, and postnatal effects of leptin on energy regulation systems, influenced by the nutritional environment. The review emphasizes leptin's role in establishing neuronal circuitry and the adiposity set-point.
In studies involving obese and diabetic mice, findings revealed that leptin acts as a satiety factor. The focus on leptin's prenatal and perinatal roles in establishing neuronal circuitry and its significance in maintaining energy balance in both humans and rodents are highlighted.
In rats and mice, maternal high-fat diet (HFD) during gestation and/or lactation, or overfeeding the pups, can affect the postnatal leptin surge and weight of the offspring. Elevated circulating leptin during the suckling period can lead to increased adiposity and weight gain in adult offspring. Leptin supplementation during early life can reprogram the body weight set point and make mice less sensitive to future increases in leptin.
When attempting to lose weight and maintain a lower body weight, changes occur in both energy intake and expenditure that work against these efforts. Changes include increased hunger, delayed satisfaction after eating, and heightened brain responses to food reward, making it harder to resist overeating. Energy expenditure also decreases as skeletal muscle becomes more efficient, and there are changes in neuroendocrine function and nervous system activity that conserve energy. These combined factors make it challenging to sustain weight loss as the body’s weight regulatory systems are biased toward defending against sustained weight loss to ensure reproductive capacity and survival.
The article points out that leptin supplementation in leptin-deficient humans and mice reversed obesity, hyperphagia, and hypometabolism and short-term administration reduced appetite, body weight, and adiposity in lean and obese mice. However, results were not linear as the effects on energy homeostasis depend on the nutritional environment and the level of leptin administration. Leptin administration during caloric restriction results in minor appetite reduction but no significant changes in energy expenditure or hormonal function. It also does not induce or sustain weight loss in humans, and its effects are not more pronounced in individuals without obesity. Leptin resistance may be present in both obese and non-obese individuals. However, in weight-reduced individuals who are weight stable, leptin repletion has shown to reverse the metabolic and behavioral factors that contribute to weight regain.
Understanding the critical roles of leptin in early development and its impact on body weight regulation has implications for dietitians in their role to prevent and treat obesity. Modifying the development of leptin-mediated neuronal circuits through interventions during fetal development, such as manipulating the intrauterine environment (maternal weight gain and diet), may reduce the risk of obesity later in life. While leptin alone may not be effective as a weight loss medication, its efficacy could be enhanced by leptin sensitizing agents or in individuals with low levels of leptin. The article calls for more long-term studies to assess the effects of leptin on successful weight maintenance. The changeability of the leptin threshold, particularly in lowering it, is still a critical question that requires further investigation. Genetic and developmental factors, along with potential interventions, may influence an individual's threshold for minimum body fat and contribute to obesity prevention. Evidence suggests that prenatal factors, such as exposure to a post-bariatric surgery intrauterine environment, can influence fatness and metabolic health in children.