Diet-induced obesity promotes infection by impairment of the innate antimicrobial defense function of dermal adipocyte progenitors

Abstract

Infections are a major complication of obesity, but the mechanisms responsible for impaired defense against microbes are not well understood. Here, we found that adipocyte progenitors were lost from the dermis during diet-induced obesity (DIO) in humans and mice. The loss of adipogenic fibroblasts from mice resulted in less antimicrobial peptide production and greatly increased susceptibility to Staphylococcus aureus infection. The decrease in adipocyte progenitors in DIO mice was explained by expression of transforming growth factor–β (TGFβ) by mature adipocytes that then inhibited adipocyte progenitors and the production of cathelicidin in vitro. Administration of a TGFβ receptor inhibitor or a peroxisome proliferator–activated receptor–γ agonist reversed this inhibition in both cultured adipocyte progenitors and in mice and subsequently restored the capacity of obese mice to defend against S. aureus skin infection. Together, these results explain how obesity promotes dysfunction of the antimicrobial function of reactive dermal adipogenesis and identifies potential therapeutic targets to manage skin infection associated with obesity.

Emerging Roles of Adipose Tissue in the Pathogenesis of Psoriasis and Atopic Dermatitis in Obesity

“…By analyzing age-related changes in dermal fat in human skin, we have found that back skin is enriched with dWAT in neonates and that human dWAT becomes gradually lost during postnatal development and aging ( Zhang et al., 2019 ), indicating that adipogenic dFBs are also lost in human skin during aging. We also have found that whereas adipocytes are normally found in the lower dermis of lean subjects, adipocytes infiltrate through the upper dermis in the back skin of subjects who are obese ( Zhang et al., 2021a ). Another study shows that overfeeding in adult humans leads to adipocyte hyperplasia in the lower body subcutaneous adipose but not in the abdominal subcutaneous adipose ( Tchoukalova et al., 2010 ), suggesting that there is a regional difference in cellular mechanisms of AT growth in obesity.…”

“…The proliferative and adipogenic potentials of preadipocytes were also negatively correlated with both BMI and adipocyte cell size of the donors ( Liu et al., 2017 ; Zhang et al., 2021a ). Work from our group or other groups has shown that TNF-α, TGFβ, and/or WNT secreted from enlarging mature adipocytes and/or infiltrated macrophages inhibit the adipogenic potential of preadipocytes and induce a proinflammatory and profibrotic phenotype in these cells, leading to impairment of adipocyte hyperplasia, amplification of tissue inflammation, and fibrosis during the chronic state of obesity ( Isakson et al., 2009 ; Liu et al., 2017 ; Zhang et al., 2021a ). Together, dysregulation of the release of adipokines and/or cytokines driven by adipocyte hypertrophy is a critical event that leads to adipose dysfunction and inflammation in obesity.…”

“…By lineage tracing experiments in mice, it has been shown that diet-induced obesity (DIO) induces a transient proliferation of preadipocytes to produce new adipocytes (hyperplasia), followed by a hypertrophic growth of adipocytes in the epidydimal WAT (the visceral fat depot in mice), whereas the expansion of sWAT primarily occurs through hypertrophy ( Jeffery et al., 2015 ). Our recent work has shown that DIO triggers an initial hyperplasia growth of dermal adipocytes from adipogenic dermal fibroblasts (dFBs) in mice, but after 2 months of DIO, adipocyte hypertrophy accounts for the majority of dWAT expansion, leading to depletion of adipogenic dFBs and domination of mature adipocytes in the skin dermis during obesity ( Zhang et al., 2021a ). Therefore, AT expands by hypertrophy with or without hyperplasia in a depot-specific manner during obesity in mice.…”

“…Recent studies from our group have identified dermal fat (dWAT) as a newly recognized layer of skin defense ( Chen et al., 2019 ), but how dWAT is related to PSO and/or AD remains largely unexplored. We have shown that antimicrobial peptide (AMP) cathelicidin is abundantly secreted from differentiating early adipocytes during adipogenesis contributing to skin innate defense against bacterial infection, and loss of adipogenesis or adipocyte hypertrophy during aging and/or obesity impairs this antimicrobial function of dWAT ( Zhang et al., 2021a , 2019 , 2015 ). AMPs represent a class of endogenous antibiotics-like proteins induced during infection or injury in host cells ( Zhang and Gallo, 2016 ).…”

The Anti-Adiposity Mechanisms of Ampelopsin and Vine Tea Extract in High Fat Diet and Alcohol-Induced Fatty Liver Mouse Models

“…The γ isoform exists in all tissues, is predominantly expressed in adipose tissue, and is essential for the differentiation and function of adipocytes [ 27 , 28 ]. A previous study reported that PPARγ was the most highly expressed and necessary in adipocytes for differentiation and is regarded as a master regulator of adipogenesis and a key regulator of gene expression in matured adipocytes [ 29 , 30 , 31 ]. Besides these, recently, lots of experiments related to obesity in whole-body PPARα − deficient mice (PPARα −/− ) and in mice lacking PPARα only in hepatocytes (PPARα hep−/− ) were performed.…”