High-Fat Diet Exacerbates Early Psoriatic Skin Inflammation Independent of Obesity: Saturated Fatty Acids as Key Players

Abstract

In obesity, hypertrophic adipocytes secrete high amounts of adipocytokines, resulting in low-grade inflammation amplified by infiltrating proinflammatory macrophages, oxidative stress, hypoxia, and lipolysis. These chronic proinflammatory conditions support the development of type II diabetes and cardiovascular diseases, but the mechanisms of obesity-related exacerbation of inflammatory skin disorders like psoriasis are unclear. In this study, we uncovered dietary saturated fatty acids (SFAs) as major risk factors for the amplification of skin inflammation, independent of obesity-related parameters such as fat mass extension, adipocytokine levels, and glucose homeostasis. Correlation analyses in a cohort of psoriasis vulgaris patients showed that free fatty acid serum level was the only obesity-associated parameter affecting disease severity. Studies in mice with high-fat diet-induced obesity with psoriasiform inflammation confirmed this critical role of free fatty acids. An increase of free fatty acids in healthy, lean mice alone was sufficient to induce an exacerbation of psoriasiform inflammation. In particular, saturated fatty acids sensitize myeloid cells to an increased inflammatory response in answer to proinflammatory stimuli, which in turn augments the activation of keratinocytes. Consequently, reduction of nutritional saturated fatty acids alone diminished the psoriatic phenotype in obese mice. Thus, our findings may open new perspectives for adjuvant dietary measures accompanying anti-inflammatory psoriasis therapies in lean and obese patients.

Hyperglycemia Is Associated with Psoriatic Inflammation in Both Humans and Mice

“…It is thus conceivable that several underlying mechanisms, including stress, are involved in the association between psoriasiform inflammation and glucose metabolism (Kotas and Medzhitov, 2015;Rorsman and Braun, 2013). A high-fat diet and/or endoplasmic reticulum stress induced by diabetic obese conditions exacerbated psoriasiform skin lesions in the IMQ-treated mouse model (Herbert et al, 2018;Nakamizo et al, 2017;Shimoura et al, 2018). We found that inducing psoriasiform features by IMQ application resulted in hyperglycemia in mice without a high-fat diet or obesity.…”

“…To determine whether inflammation associated with psoriasis influences glucose metabolism, we took advantage of an imiquimod (IMQ)-induced mouse model. Although there are some differences between the model mice and patients, the IMQinduced model is widely used (Herbert et al, 2018;Shimoura et al, 2018;Stockenhuber et al, 2018). IMQ is a TLR-7/8 ligand, and its application to the skin induces both psoriasis-like skin lesions and systemic inflammation, such as production of cytokines (Grine et al, 2015;Roller et al, 2012;van der Fits et al, 2009).…”

A Western Diet, but Not a High-Fat and Low-Sugar Diet, Predisposes Mice to Enhanced Susceptibility to Imiquimod-Induced Psoriasiform Dermatitis

“…The fact that HFD-fed mice have more body weight gain but less inflammation in response to IMQ than WD-fed mice strongly suggests obesity alone is not sufficient to promote PsD in the skin. Intriguingly, a recent study indicated that a high-dietary-fat diet exacerbates psoriatic skin inflammation independent of obesity (Herbert et al, 2018). Another study, using different chow recipes, also Western Diet Exacerbates Psoriasis concluded that high dietary fats exacerbate IMQ-induced psoriasis-like dermatitis in mice (Higashi et al, 2018).…”

Saturated Fatty Acids as Possible Key Amplifiers of Psoriatic Dermatitis

“…Using a mouse psoriasis model, Herbert et al (2018) provide evidence that regulation of dietary SFAs attenuates psoriatic dermatitis. They first examined the relationship between various blood markers associated with obesity (including FFAs, hemoglobin A1c, and insulin) and the severity of psoriasis.…”