Potential role ofFoxO1 and mTORC1 in the pathogenesis ofWestern diet‐induced acne

Abstract

Acne in adolescents of developed countries is an epidemic skin disease and has currently been linked to the Western diet (WD). It is the intention of this viewpoint to discuss the possible impact of WD-mediated nutrient signalling in the pathogenesis of acne. High glycaemic load and dairy protein consumption both increase insulin/insulin-like growth factor-1 (IGF-1) signalling (IIS) that is superimposed on elevated IGF-1 signalling of puberty. The cell's nutritional status is primarily sensed by the forkhead box transcription factor O1 (FoxO1) and the serine/threonine kinase mammalian target of rapamycin complex 1 (mTORC1). Increased IIS extrudes FoxO1 into the cytoplasm, whereas nuclear FoxO1 suppresses hepatic IGF-1 synthesis and thus impairs somatic growth. FoxO1 attenuates androgen signalling, interacts with regulatory proteins important for sebaceous lipogenesis, regulates the activity of innate and adaptive immunity, antagonizes oxidative stress and most importantly functions as a rheostat of mTORC1, the master regulator of cell growth, proliferation and metabolic homoeostasis. Thus, FoxO1 links nutrient availability to mTORC1-driven processes: increased protein and lipid synthesis, cell proliferation, cell differentiation including hyperproliferation of acroinfundibular keratinocytes, sebaceous gland hyperplasia, increased sebaceous lipogenesis, insulin resistance and increased body mass index. Enhanced androgen, TNF-α and IGF-1 signalling due to genetic polymorphisms promoting the risk of acne all converge in mTORC1 activation, which is further enhanced by nutrient signalling of WD. Deeper insights into the molecular interplay of FoxO1/mTORC1-mediated nutrient signalling are thus of critical importance to understand the impact of WD on the promotion of epidemic acne and more serious mTORC1-driven diseases of civilization.

Beyond acne: Current aspects of sebaceous gland biology and function

“…While human sebocytes may also express FoxO1, few relevant data exist until now [71,72]. In adipocytes, FoxO1 directly interacts with PPARγ to inhibit adipocyte differentiation and substantial evidence indicate a pivotal role FoxO1 in lipid homeostasis, regulation of oxidative stress, cell differentiation and apoptosis [70].…”

“…In adipocytes, FoxO1 directly interacts with PPARγ to inhibit adipocyte differentiation and substantial evidence indicate a pivotal role FoxO1 in lipid homeostasis, regulation of oxidative stress, cell differentiation and apoptosis [70]. It has been proposed that acne and increased sebaceous lipogenesis are associated with a relative nuclear deficiency of FoxO1 caused by increased growth hormone (GH)/insulin/IGF-1/or FGFR2 signaling [72].…”

Influência do Índice de Massa Corporal e da Dieta na Fisiopatologia da Acne Vulgaris

“…O Fox01 nuclear é regulado pela insulina e reduz também a expressão do recetor da hormona de crescimento e síntese hepática do IGF-1. 8,12 O FoxO1 nuclear tem também um importante papel na inibição do mTORC1. Por outro lado a insulina, o IGF-1, a testosterona, a leucina e outros aminoácidos essenciais de cadeia ramificada (BCAAs), como a glutamina e o ácido palmí-tico livre, um ácido gordo saturado livre, ativam o mTORC1.…”

“…8 A literatura recente tem demonstrado que os alimentos podem influenciar as doenças dermatológicas de modos diferentes, referindo existir associação entre a dieta e a acne vulgar. 3,4,8,12 A dieta ocidental em particular, constituída por carbohidratos com alto teor glicémico, leite de vaca e ácidos gordos saturados, tem sido indicada como uma das grandes responsáveis pelo aumento sérico da IGF-1, estados da hiperinsulinémia e inibição do Fox01. Por outro lado, a dieta ocidental e a acne estão associadas à existência de índice de massa corporal (IMC) excessivo.…”

“…Um alto IMC é um fator major da síndrome metabólica, que por sua vez está associada à existência de resistência à insulina. 12 Tem-se procurado perceber qual o papel e a importância da dieta ocidental e do IMC no aparecimento da acne vulgar, bem como no esclarecimento da sua fisiopatologia. Assim, o objetivo deste trabalho é rever a literatura recente que aborda a fisiopatologia da acne vulgar e a relação entre a acne e os diferentes alimentos da dieta e o IMC.…”