Abstract
Atopic dermatitis is a chronic inflammatory skin condition marked by intense itching and a weakened skin barrier. The compromised skin barrier often leads to exaggerated immune responses and greater sensitivity to allergens. Previous studies have already implicated a link between obesity and atopic dermatitis; however, the mechanisms linking obesity to atopy are not yet well understood. We propose that obesity impairs skin barrier function, facilitating allergen penetration in the skin and triggering systemic and local allergic sensitization. We used a diet-induced obesity mouse model to examine skin barrier integrity and immune responses in both steady-state and inflammatory conditions. In order to induce dermatitis or food allergy, we epicutaneously applied MC903 or ovalbumin, respectively. We observed that obesity significantly alters skin barrier physiology, as indicated by increased transepidermal water loss in obese animals. Over time, we observed a decrease in key skin barrier proteins-preceding overt cutaneous inflammation, further indicating a loss of barrier integrity during obesity. Interestingly, skin barrier breakdown was independent of changes to the microbiome. On a cellular level, immune profiling revealed a shift towards a type 17 helper T-cell response bias, although this shift did not coincide with an increase in cytokine production under steady-state conditions. Topical application of MC903 in obese animals led to increased ear swelling and a pronounced Th17-biased inflammatory response compared to lean counterparts. Our findings show that obesity weakens the skin barrier, facilitating increased allergen penetration and allergic sensitization. The Th17-skewed immune environment in obese animals may also amplify inflammatory responses to allergens and act as a feed-forward loop to further disintegrate the skin barrier. This study highlights how obesity-induced skin barrier dysfunction contributes to allergic conditions like atopic dermatitis and may be therapeutically targeted by barrier restoration.