Leptin is a hormone primarily produced by the adipose tissue in proportion to the size of fat stores, with a primary function in the control of lipid reserves. Besides adipose tissue, leptin is also produced by other tissues, such as the stomach, placenta, and mammary gland. Altogether, leptin exerts a broad spectrum of short, medium, and long-term regulatory actions at the central and peripheral levels, including metabolic programming effects that condition the proper development and function of the adipose organ, which are relevant for its main role in energy homeostasis. Comprehending how leptin regulates adipose tissue may provide important clues to understand the pathophysiology of obesity and related diseases, such as type 2 diabetes, as well as its prevention and treatment. This review focuses on the physiological and long-lasting regulatory effects of leptin on adipose tissue, the mechanisms and pathways involved, its main outcomes on whole-body physiological homeostasis, and its consequences on chronic diseases.

A main challenge in nutritional studies is the valid and reliable assessment of food intake, as well as its effects on the body. Generally, food intake measurement is based on self-reported dietary intake questionnaires, which have inherent limitations. They can be overcome by the use of biomarkers, capable of objectively assessing food consumption without the bias of self-reported dietary assessment. Another major goal is to determine the biological effects of foods and their impact on health. Systems analysis of dynamic responses may help to identify biomarkers indicative of intake and effects on the body at the same time, possibly in relation to individuals’ health/disease states. Such biomarkers could be used to quantify intake and validate intake questionnaires, analyse physiological or pathological responses to certain food components or diets, identify persons with specific dietary deficiency, provide information on inter-individual variations or help to formulate personalized dietary recommendations to achieve optimal health for particular phenotypes, currently referred as “precision nutrition.” In this regard, holistic approaches using global analysis methods (omics approaches), capable of gathering high amounts of data, appear to be very useful to identify new biomarkers and to enhance our understanding of the role of food in health and disease.

Although leptin is a hormone mainly produced by the adipose tissue, it is also produced by the gastric mucosa and the mammary epithelium and is present in maternal milk. The effects of milk leptin on the neonate are not known. The purpose of the investigation was to evaluate the short-term effects of the administration of a single oral dose of leptin on 4-d-old rats as well as the effects of chronic supplementation during the lactation period with a daily oral dose of leptin (equivalent to 5 times the amount of leptin ingested normally from maternal milk during the suckling period) on body weight, the gastric leptin system, gastric food content, and thermogenic capacity. Our results show that the administration of a single oral dose of 4 ng of leptin to 4-d-old rats produces a short-term increase in leptin levels in the stomach and serum and a decrease in the weight of the gastric contents. Pups treated with a daily oral dose of leptin during the whole lactation period showed, at the end of the suckling period, compared with controls, lower gastric contents, lower leptin production by the stomach and the sc adipose tissue, and lower thermogenic capacity in brown adipose tissue. We conclude that oral leptin is absorbed by the immature gastric epithelium of the neonate, and this leptin exerts clear biological effects, down-regulating endogenous leptin production and playing a potential role in the short-term control on food intake during the lactation period.