Killer fat

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Science  02 Jan 2015:
Vol. 347, Issue 6217, pp. 26-27
DOI: 10.1126/science.aaa4567

The skin, the largest organ in the human body, plays a critical role as a barrier to pathogen entry into tissues. Its disruption can lead to invasive bacterial disease. When this does happen, many resident cells in the skin's dermal layers, including immune cells, limit bacterial colonization. The role of fat cells (adipocytes) in the skin's host defense function is only recently emerging. On page 67 in this issue, Zhang et al. (1) add to this view by showing that dermal adipocytes participate directly in innate immunity against Staphylococcus aureus (see the figure).

The skin is composed of an outermost stratified epidermis and an underlying dermis that is inundated with vascular tissue, fibroblasts, phagocytes, lymphocytes, and adipose tissue. Epidermal keratinocytes produce antimicrobial peptides that kill invading pathogens and, in concert with dermal phagocytes, promote pathogen clearance (2).

S. aureus is a commonly found commensal bacterium on human skin. Infection with methicillin-resistant S. aureus (MRSA) is responsible for more deaths in the United States than any other infectious pathogen (3). Susceptibility to S. aureus infection in the skin (and lung) (2, 4) has been associated with decreased production of cytokines in these organs that regulate the production of antimicrobial peptides by epithelial and immune cells (5, 6). S. aureus also triggers the production of interleukin-6 by adipocytes, a cytokine that stimulates the production of the bacteriostatic, iron-binding protein hepcidin (7). This suggests a role for these cells in host defense against this pathogen (8, 9).

A breach in the epidermis can cause the underlying dermis to become infected with S. aureus, resulting in dangerous inflammation (cellulitis and fasciitis). To model this, Zhang et al. used subcutaneous injection of MRSA in mice to introduce infection directly into the underlying dermis. MRSA infection results in the recruitment of myeloid, lymphoid, and mast cells, all of which have been implicated in the bacterial clearance and successful host defense. However, the dermis is also characterized by connective tissue containing fibroblasts and adipocytes. The authors noted that MRSA infection caused a marked increase in dermal adipose tissue in part due to hypertrophy and proliferation of the adipocytes. Adipogenesis was partly due to expression of the transcription factor zinc finger protein 423 (ZFP423), whose expression controls another transcription factor called peroxisome proliferator-activated receptor gamma (PPAR-γ). Using mice with a mutation in ZFP423, or treating normal mice with a PPAR-γ inhibitor, Zhang et al. reveal the requirement for these transcription factors in the expansion of dermal adipose in response to MRSA infection. Blocking adipogenesis in mouse skin also impaired host defenses against MRSA infection.

Responding to the breach.

Disruption of the epidermis can introduce pathogens into the dermis. This provokes the proliferation of adipocytes (involving transcription factors ZFP423 and PPAR-γ). Adipocytes secrete cathelicidin, whose anti-staphylococcal activity can control skin infections.


Cathelicidin is an antimicrobial peptide with anti-staphylococcal activity. By showing that a murine adipocyte cell line and primary human adipocytes produce this peptide in response to S. aureus conditioned media or inactivated bacteria, Zhang et al. suggest that fat cells can directly sense the pathogen. As well, conditioned media from wild-type murine adipocytes, but not adipocytes from cathelicidin-deficient mice, controlled S. aureus growth in mice. Animals with deficient adipogenesis (mice lacking ZFP423 or mice treated with the PPAR-γ inhibitor) had impaired cathelicidin production upon S. aureus infection and were as susceptible to infection as cathelicidin-deficient mice. Moreover, PPAR-γ inhibition in cathelicidin-deficient mice did not exacerbate infection, suggesting that the major anti-staphylococcal protein controlled by adipogenesis is cathelicidin.

In addition to its well-known role in growth and metabolism, adipocytes play key roles in controlling soft tissue infection. From an evolutionary perspective, this makes sense, as this function would provide the host with an additional layer of defense against an abraded or traumatic wound to the epidermis. However, there is likely a healthy amount of dermal fat and an unhealthy amount. Zhang et al. address this in part by studying a high-fat diet. Interestingly, induction of adipogenesis in mice through a high-fat diet also increased the production of cathelicidin by the proliferating adipocytes. However, mice harboring disabling mutations in the receptor for leptin—a hormone produced by fat cells that suppresses food intake—gain weight and develop type 2 diabetes, but are more susceptible to S. aureus infection (10). Likewise, in humans, obesity has been associated with an increased risk of skin and soft tissue infection (11). One possible explanation for this discrepancy is that insulin resistance or other aspects of metabolic syndrome perturb the infection-adipogenesis-cathelicidin pathway identified by Zhang et al. Thus, signaling by adipose-derived hormones that control energy expenditure (adipokines) could influence the expression of cathelicidin. This antimicrobial peptide also is posttranslationally cleaved to its active form, a process that that may also be influenced by obesity and metabolic syndrome.

The mechanism underlying the recognition of S. aureus by adipocytes remains unclear, although it likely involves tolllike receptor 2 (TLR2). Adipocytes express many members of the toll-like receptor family, including TLR2 (9, 12), which recognizes lipopeptides produced by bacteria. This may be an operative pathway that controls cathelicidin production. Moreover, a TLR2-ZFP423-PPAR-γ-cathelicidin pathway might be augmented pharmacologically by PPAR-γ agonists, thereby increasing host resistance to infection in susceptible individuals such as those with diabetes and metabolic syndrome.


  1. Acknowledgments: J.F.A. acknowledges support from NIH grant R01HL107380; J.K.K. is supported by NIH grant R37HL079142.
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