The Leptin System and Diet: A Mini Review of the Current Evidence

• Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, United States

Leptin promotes satiety and modulates energy balance and weight. Diet-induced obesity leads to leptin resistance, exacerbating overeating. We reviewed the literature on the relationship between diet and leptin, which suggests that addressing leptin resistance through dietary interventions can contribute counteracting obesity. Albeit some limitations (e.g., limited rigor, small samples sizes), studies in animals and humans show that diets high in fat, carbohydrates, fructose, and sucrose, and low in protein are drivers of leptin resistance. Despite methodological heterogeneity pertaining to this body of literature, experimental studies show that energy-restricted diets can reduce leptinemia both in the short and long term and potentially reverse leptin resistance in humans. We also discuss limitations of this evidence, future lines of research, and implications for clinical and public health translations. Main limitations include the lack of a single universally-accepted definition of leptin resistance, and of adequate ways to accurately measure it in humans. The use of leptin sensitizers (drugs) and genetically individualized diets are alternatives against leptin resistance that should be further researched in humans. The tested very-low-energy intervention diets are challenging to translate into wide clinical or population recommendations. In conclusion, the link between nutritional components and leptin resistance, as well as research indicating that this condition is reversible, emphasizes the potential of diet to recover sensitivity to this hormone. A harmonized definition of leptin resistance, reliable methods to measure it, and large-scale, translational, clinical, and precision nutrition research involving rigorous methods are needed to benefit populations through these approaches.

Introduction

Discovered in 1994, leptin is an adipokine, a protein that functions as a hormone. Two major producers and secretors of leptin are the adipose tissue and the gastric mucosa. Leptin promotes satiety and has a central role in energy balance and weight management. A primary leptin signaling pathway is its interaction with the hypothalamus, which modulates the central nervous system to regulate metabolic homeostasis. Leptin also interacts with insulin, impacting glucose and lipid homeostasis. In normal physiological conditions, serum leptin increases in the fed state, decreases in the fasted state, and is directly correlated with total body fat mass: if there is more adipose tissue, there is more leptin, thereby reflecting long-term energy availability. Furthermore, in conjunction with its long receptor expressed by most immune cells, leptin has proinflammatory activity.

The role of leptin in diet-related disease has been well-studied. This mini review summarizes a significant body of literature documenting the interconnection between leptin and food intake and examines the evidence around the paradoxical phenomenon known as leptin resistance (LR), whereby chronically elevated leptin levels lead to an inefficient transport of leptin into the brain, reduced hypothalamic leptin receptor (LepRb) expression, alteration of leptin signaling cascade in the hypothalamus, among other mechanisms that impair leptin function over time. With research pointing toward leptin sensitization as a promising weight loss intervention, we primarily discuss nutritional interventions aimed at normalizing leptin levels and sensitivity. Gaps and limitations in the current evidence, as well as areas for future research and clinical translation, are also discussed.

Leptin Physiology

Leptin circulates in proportion to body energy stores and food availability. When energy reserves are high, leptin is secreted by adipocytes into the bloodstream (constitutive secretion). Gastric leptin secretion (regulated) rapidly responds to the stimuli caused by food intake. Being this hormone resistant to proteolysis in the intestinal tract, gastric leptin contributes with a large part of the circulating leptin levels, but especially with those occurring at food ingestion and digestion.

Once in the bloodstream, leptin crosses the blood–brain barrier to bind its receptor in the hypothalamus to signal satiety and decrease hunger and food intake. Aside from the central action of leptin described above, this hormone has peripheral actions occurring in different tissues. For example, interacting with cholecystokinin in the stomach, leptin increases vagal afferent activity controlling the gastric emptying which in turn contributes to satiety. At intestinal level in postprandial conditions, leptin boosts carbohydrate and protein absorption through an increased expression of glucose transporters (GLUT-2, GLUT-5, and sodium-glucose cotransporter-1) and the activation of the proton-dependent di- and tri-peptide transporter PepT1. Conversely, leptin diminishes lipid release into the bloodstream after downregulating apolipoproteins. Another important function of leptin is to reduce ectopic accumulation of fat by stimulating fatty acid oxidation in the liver and muscular tissue.

When adipose reserves or food availability are low, leptin levels decrease, thereby increasing food intake to ensure a steady supply of metabolic fuel. It is reasonable to think that leptin decrements to increase food intake produce a stronger signal than the one produced by a rise of this hormone to reduce food intake as a survival function resulting from the long-term evolutionary challenges dominated by food shortage. Along with the rationale above, the correlation between leptin and body weight suggests that leptin signaling evolved as an indicator of high energy reserves and a lessened need for food intake. However, the current body of evidence paints a more complex picture.

Leptin Resistance and Diet-Induced Obesity

Diet-induced obesity (DIO) interferes with the hormonal regulation of body weight and hunger, as leptin resistance and hyperleptinemia frequently co-exist. Individuals with mutations in the leptin gene, regardless of their obesity status, have been treated with exogenous sources of leptin to restore normal function. It was suggested that exogenous sources of leptin could also be used in individuals with obesity, who were thought to lack sufficient leptin. However, this proved to be ineffective. Recent research clarified that individuals with DIO tend to have chronic hyperleptinemia: elevated, rather than reduced, circulating leptin for their adipose mass. Animal models suggest that when circulating leptin levels are chronically elevated, hypothalamic leptin receptors become desensitized, akin to insulin resistance seen in type 2 diabetes. In LR, the hypothalamus becomes increasingly less responsive to leptin, hunger remains elevated, and food intake does not decrease although energy in the form of adipose is abundant. Multiple mechanisms compromising the signaling cascade and action of leptin and its receptor in obesity conditions have been described, although specific pathways remain unclear.