Leptin, Acting at Central Level, Increases FGF21 Expression in White Adipose Tissue via PPARβ/δ.

Lorena Mazuecos,Antonio Andrés,Cristina Pintado,Nilda Gallardo,Blanca Rubio,Eduardo Guisantes-Batán

doi:10.3390/ijms22094624

Lorena Mazuecos, Antonio Andrés + Show 4 more

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https://doi.org/10.3390/ijms22094624

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Abstract

The altered function of adipose tissue can result in obesity, insulin resistance, and its metabolic complications. Leptin, acting on the central nervous system, modifies the composition and function of adipose tissue. To date, the molecular changes that occur in epididymal white adipose tissue (eWAT) during chronic leptin treatment are not fully understood. Herein we aimed to address whether PPARβ/δ could mediate the metabolic actions induced by leptin in eWAT. To this end, male 3-month-old Wistar rats, infused intracerebroventricularly (icv) with leptin (0.2 μg/day) for 7 days, were daily co-treated intraperitoneally (ip) without or with the specific PPARβ/δ receptor antagonist GSK0660 (1 mg/kg/day). In parallel, we also administered GSK0660 to control rats fed ad libitum without leptin infusion. Leptin, acting at central level, prevented the starvation-induced increase in circulating levels of FGF21, while induced markedly the endogenous expression of FGF21 and browning markers of eWAT. Interestingly, GSK0660 abolished the anorectic effects induced by icv leptin leading to increased visceral fat mass and reduced browning capacity. In addition, the pharmacological inhibition of PPARβ/δ alters the immunomodulatory actions of central leptin on eWAT. In summary, our results demonstrate that PPARβ/δ is involved in the up-regulation of FGF21 expression induced by leptin in visceral adipose tissue.

Highlights

Whole Body Pharmacological Inhibition of PPARβ/δ Reduced the Effects of Central Leptin in Initially, wePPARβ/δ wantedExpression to confirm the ability of exogenous central leptin infusionActions to ac-of Leptin in epididymal white adipose tissue (eWAT), and Abolished the Anorexigenic and Adipostatic tivate hypothalamic leptin signaling
We analyze the implication of PPARβ/δ as a potential mediator of both central and peripheral metabolic, inflammatory, and immunomodulatory actions of leptin acting on the CNS
Because currently little is known about the role of PPARβ/δ in visceral WAT, we focus our attention on the in vivo blockage of PPARβ/δ in eWAT

Summary

Introduction

Leptin is mainly synthesized and secreted by white adipose tissue in proportion to fat content, acting as an energy store signal. Once in circulation, it reaches hypothalamic centers and controls food intake, energy homeostasis, body fat, and immune response by altering the secretion of hypothalamic neuropeptides [1,2,3,4]. Acting through the sympathetic nervous system (SNS) and the neuroendocrine hypothalamic–pituitary–thyroid (HPT) axis, leptin increases lipolysis and promotes adaptive thermogenesis in white adipose tissue, a fact that leads to an increase in energy expenditure and decrease fat stores [6,7,8]. Chronic leptin treatment corrects hyperphagia, impaired lipid metabolism, and thermogenesis in ob/ob mice [9]

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