Palmitoylethanolamide Promotes White-to-Beige Conversion and Metabolic Reprogramming of Adipocytes: Contribution of PPAR-α.

Chiara Annunziata,Maria Carmela Ferrante,Anna Monnolo,Antonio Giordano,Claudio Pirozzi,Adriano Lama,Antonella Bordin,Federica Comella,Alessandra Pelagalli,Rosaria Meli,Angelo Iossa,Elena De Falco,Saverio Cinti,Giuseppina Mattace Raso,Martina Senzacqua,Maria Pina Mollica

doi:10.3390/pharmaceutics14020338

Abstract

The potential role of brown and beige adipose tissue against obesity has been recognized. Browning, or beiging of white adipose tissue (WAT) is associated with the remodeling of adipocytes and the improvement of their metabolic and secretory functions. Here, palmitoylethanolamide (PEA) restore the plasticity of brown and white adipocytes impaired in mice on a high-fat diet (HFD). Young male C57Bl/6J mice were fed with control (STD) diet or HFD for 12 weeks. Ultramicronized PEA (30 mg/kg/die p.o.) was administered for an additional 7 weeks, together with HFD. PEA recovered interscapular brown fat morphology and function, increasing UCP1 positivity, noradrenergic innervation, and inducing the mRNA transcription of several specialized thermogenic genes. PEA promotes the beige-conversion of the subcutaneous WAT, increasing thermogenic markers and restoring leptin signaling and tissue hormone sensitivity. The pivotal role of lipid-sensing peroxisome proliferator-activated receptor (PPAR)-α in PEA effects was determined in mature 3T3-L1. Moreover, PEA improved mitochondrial bioenergetics in mature adipocytes measured by a Seahorse analyzer and induced metabolic machinery via AMPK phosphorylation. All these outcomes were dampened by the receptor antagonist GW6471. Finally, PEA induced adipogenic differentiation and increased AMPK phosphorylation in human adipose-derived stromal cells (ASCs) obtained from subcutaneous WAT of normal-weight patients and patients with obesity. We identify PEA and PPAR-α activation as the main mechanism by which PEA can rewire energy-storing white into energy-consuming brown-like adipocytes via multiple and converging effects that restore WAT homeostasis and metabolic flexibility.

Highlights

In mammals, white (WAT) and brown (BAT) adipose tissues with opposing functions coexist into multiple visceral and subcutaneous fat depots
peroxisome proliferator-activated receptor (PPAR)-α connects the nutritional inputs to the activation of specific cellular gene programs, that are involved in whole-body carbohydrate and lipid metabolism, increasing free fatty acid oxidation, improving insulin resistance and energy expenditure in obesity [7,8]
Our data demonstrate that PEA treatment promoted the interscapular BAT (iBAT) thermogenic adaptation to the excessive energy gained from the high-fat diet (HFD), increasing the number of UCP1-positive clusters of brown adipocytes associated with the recovery of the typical BAT morphology

Summary

Introduction

White (WAT) and brown (BAT) adipose tissues with opposing functions (lipid storage vs. thermogenesis) coexist into multiple visceral and subcutaneous fat depots. The adipose tissue is a convertible organ able to plastically adapt its metabolic, endocrine, and thermogenic functions to endogenous or exogenous stimuli [1]. Some adipocyte progenitors and white adipocytes residing into WAT depots are capable of browning or beiging, by which thermogenic brown-like adipocytes emerge in response to distinctive stimuli [3]. This phenotypic change of the adipose organ has proved to be effective in the protection against the metabolic disorders associated with obesity and diabetes. A close interplay interestingly exists among adipocytes, sympathetic nervous and immune systems, and this crucial crosstalk is deeply affected when obesity occurs [9]

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