Leptin: Anti-Obesity or Immune System Secret?

Leptin: Anti-Obesity Hormone or well-kept Secret to the Immune System?
The discovery of leptin (Greek root leptos, meaning thin) (1), the “anti-obesity hormone,” (2) raised hope that there might actually be a simple cure for obesity. Though the hormone was first documented in 1958 (1), an explosion of research through the 1990s to the present has revealed that this hope was premature. Obesity is undeniably a complex condition that is closely intertwined with biology/genetics, environmental conditions, and social/behavioral factors. Thus, there is no “simple” cure for obesity, and unfortunately, leptin’s role in any “cure” at all remains speculative. While the neurohormonal role of leptin in human metabolism and adipose tissue biology is now fairly well established, a less well-known role of leptin in human physiology appears to be rooted in the immune system. This article will provide a short overview of leptin, emphasizing on its role in immunity.

Leptin is expressed in white adipose tissue, the stomach, placenta, and possibly the mammary gland, with receptors throughout human tissues (2). It is best known as a cytokine-like hormone produced by adipose tissue (3). There is a positive relationship between levels of leptin and level of adiposity (1), and in this way, it is able to communicate information on energy availability (4). Leptin activates specific areas in the central nervous system, particularly the hypothalamus, to decrease food intake, increase energy expenditure, influence metabolism of fat and glucose, and alter neuroendocrine function. It was originally thought that obesity could be a leptin-deficient state, and that peripheral or central administration of the hormone could induce satiety, thus decreasing food intake. However, it has since been documented that persons who are leptin-deficient represent only a small minority of obese individuals (2). Beyond its role in energy homeostasis, leptin plays a role in angiogenesis, bone formation, and reproduction (3), demonstrating a wide range of biological responses.

Recent investigation over the last decade has confirmed that leptin plays an essential role in 3 critical phases of immune response, including in B-cell ontogeny, and in both innate and adaptive immune responses. Leptin’s part in immunity was recently highlighted through the clinical observation that children with congenital leptin-deficiency manifested aberrant immune function through their high incidence of infections and infection-related deaths. In fact, leptin administration in these children has now been shown to correct many abnormalities of the immune system (Farooqi, 2002 in (3)). On the level of B-cell ontogeny, human bone marrow stromal cells have been shown to express leptin, and leptin is now understood to directly enhance the creation and distribution of hematopoeic stem cells and lymphoid precursor cells. In innate immunity, leptin acts upon antigen-presenting (dendritic) cells (DC), natural killer (NK) cells, and neutrophils. For example, human studies have shown that leptin signaling promotes DC maturation and enhances their survival (3). In NK cells, leptin is involved with all phases of cell development, proliferation, and death (4). Leptin also enhances macrophage migration to wound sites, and stimulates chemotaxis in neutrophils. In adaptive immunity, leptin appears to modulate T-cell immune responses, and it attenuates apoptosis in both T and B lymphocytes, promoting a longer survival for these cells (3). Leptin may also modulate autoimmune conditions. It is currently being studied in the context of rheumatoid arthritis and multiple sclerosis (3;4).

In conclusion, while leptin’s neuroendocrine function remains intriguing because of its association with eating and satiety, its critical role in the immune system is only just beginning to be understood. In the context of obesity and its associated immune functions, leptin poses a particular paradox since the majority of obese persons have plentiful levels of leptin, yet they tend to be more susceptible to infections and impaired wound healing (4). Instead of its potential as the “anti-obesity” hormone, it is possible that leptin may instead be therapeutic for immune disorders in the future. TLH, RN

(1) Caro JF, Sinha MK, Kolaczynski JW, Zhang PL, Considine RV. Leptin: the tale of an obesity gene. Diabetes 1996; 45(11):1455-1462.
(2) Mantzoros CS. The role of leptin in human obesity and disease: a review of current evidence. Ann Intern Med 1999; 130(8):671-680.
(3) Lam QL, Lu L. Role of leptin in immunity. Cell Mol Immunol 2007; 4(1):1-13.
(4) Matarese G, Moschos S, Mantzoros CS. Leptin in immunology. J Immunol 2005; 174(6):3137-3142.