Leptin as a key regulator of the adipose organ

Abstract

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.

Keywords: Adipose organ; Adiposity; Development; Energy homeostasis; Leptin; Metabolic programming.

Fig. 1

Leptin action on lipid metabolism and adipogenesis. Leptin is able to activate lipolysis in white adipose tissue (WAT), by the increase of ATGL (adipose triglyceride lipase) and HSL (hormone sensitive lipase) expression, both acting centrally activating sympathetic nervous system (SNS) and by a direct action on WAT, through β-adrenergic receptors (β-AR). Moreover, leptin directly stimulates fatty acid (FA) oxidation, by the increase of the expression of the genes coding for PPARα (peroxisome proliferator-activated receptor alpha), PGC1α (peroxisome proliferator-activated receptor-gamma coactivator 1alpha) and CPT1 (Carnitine palmitoyltransferase 1), among other proteins, and downregulates lipogenesis, decreasing the expression of SREBP1 (sterol regulatory element-binding protein 1), FASN (fatty acid synthase), ACC1 (acetyl-CoA carboxylase), etc., in WAT. In addition, leptin has been shown to exert direct actions stimulating pre-adipocyte differentiation, mainly through the activation of PPARγ2 (peroxisome proliferator-activated receptor gamma 2) and C-FOS, into mature adipocytes

Fig. 2

Leptin action on thermogenesis and browning in the adipose tissues. Leptin has been described to activate thermogenesis in brown adipose tissue (BAT), increasing UCP1 (uncoupling protein 1) production. It also exerts browning stimulation in white adipose tissue (WAT), leading to the formation of beige adipocytes, with a greater number of mitochondria, and expressing UCP1 and other markers of browning, such as PRDM16 (PR/SET domain 16). Leptin seems to exert these processes mainly acting on specific leptin-responsive neurons of the central nervous system that regulate sympathetic nervous system outflow to BAT and WAT, but direct/autocrine effects of leptin may also be involved

Fig. 3

Putative roles of embryonic and extraembryonic leptin on foetal and adipose tissue development. The placenta expresses both leptin and its full signalling capacity receptor (LEPRb), regulating critical functions of placenta during pregnancy, including amino acid (AA) transport capacity, related to foetal growth. Present evidence suggests that leptin levels in umbilical cord (UC) are a marker of adiposity in the neonates and may be putatively related to less adiposity accretion, at least in early infancy. Leptin produced by the foetus has been suggested to be related to the regulation of metabolic programming through brain (particularly hypothalamus) and adipose tissue (AT). More recently, preliminary evidence has pointed out the possibility (in a rodent model) that leptin in amniotic fluid (AF) in late gestation might have a putative physiological role in near-term foetuses, trough stomach leptin internalization, after swallowing

Fig. 4

Programming effects of leptin during lactation on white adipose tissue (WAT) and brain. Leptin intake during lactation has been described to exert neurotrophic actions, and is necessary for the proper development of hypothalamic circuits that are involved in body weight control. Leptin action during lactation is also associated with increased central leptin sensitivity, which improves the later control of energy balance. Moreover, leptin during the suckling period regulates innervation, growth and cellularity of WAT, and improves hormone signalling in this tissue, including that of leptin itself. Therefore, the intake of adequate doses of leptin during the suckling period leads to an improvement in the characteristics and functionality of the adipose tissue, programming it for a greater capacity to adapt and respond to different environmental conditions. These effects, together with those it exerts on the development of the hypothalamus, as well as on other tissues, result in a better ability to control energy homeostasis and prevent metabolic syndrome-related alterations

Fig. 5

Overview of leptin actions in the adipose organ. Leptin exerts central actions, modulating energy homeostasis and influencing multiple endocrine actions, and peripheral actions in different tissues. In the adipose organ, leptin exerts key regulatory actions through direct or indirect mechanisms, with short/medium- and long-term implications. Leptin promotes adipogenesis, lipolysis, fatty acid oxidation, apoptosis, browning, and stimulates BAT thermogenesis. At high concentrations, leptin also stimulates the production of pro-inflammatory cytokines and promotes inflammation. Moreover, during critical windows of development, leptin may exert central neurotrophic actions, affecting leptin-sensitive brain circuits involved in adipose tissue regulation, which can lead to morphological and physiological changes in the adipose tissue, with long-lasting consequences for later function and metabolic health. Therefore, adequate amounts of leptin during the perinatal period, both during the foetal and suckling periods, seem to be essential for the proper development of the adipose organ and may also compromise later leptin action. A better understanding of the mechanisms and actions of leptin in the adipose organ, as well as in other target tissues, may lead to new approaches in obesity prevention and treatment since the early stages of life