Can the skin make you fat? A role for the skin in regulating adipose tissue function and whole-body glucose and lipid homeostasis

Caton, Paul; Evans, Elizabeth; Philpott, Michael P.; Hannen, Rosalind

doi:10.1016/j.coph.2017.08.011

Cited by 11 publications

(10 citation statements)

References 68 publications

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“…Chronic inflammatory skin disease is also associated with metabolic syndrome [5][6][7]. However, the mechanism is under discussion, and the contribution of AT is still unclear.…”

Section: Introductionmentioning

confidence: 99%

Systemic Dermatitis Model Mice Exhibit Atrophy of Visceral Adipose Tissue and Increase Stromal Cells via Skin-Derived Inflammatory Cytokines

Mizutani

Shirakami

Ichishi

et al. 2020

IJMS

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Adipose tissue (AT) is the largest endocrine organ, producing bioactive products called adipocytokines, which regulate several metabolic pathways, especially in inflammatory conditions. On the other hand, there is evidence that chronic inflammatory skin disease is closely associated with vascular sclerotic changes, cardiomegaly, and severe systemic amyloidosis in multiple organs. In psoriasis, a common chronic intractable inflammatory skin disease, several studies have shown that adipokine levels are associated with disease severity. Chronic skin disease is also associated with metabolic syndrome, including abnormal tissue remodeling; however, the mechanism is still unclear. We addressed this problem using keratin 14-specific caspase-1 overexpressing transgenic (KCASP1Tg) mice with severe erosive dermatitis from 8 weeks of age, followed by re-epithelization. The whole body and gonadal white AT (GWAT) weights were decreased. Each adipocyte was large in number, small in size and irregularly shaped; abundant inflammatory cells, including activated CD4+ or CD8+ T cells and toll-like receptor 4/CD11b-positive activated monocytes, infiltrated into the GWAT. We assumed that inflammatory cytokine production in skin lesions was the key factor for this lymphocyte/monocyte activation and AT dysregulation. We tested our hypothesis that the AT in a mouse dermatitis model shows an impaired thermogenesis ability due to systemic inflammation. After exposure to 4 °C, the mRNA expression of the thermogenic gene uncoupling protein 1 in adipocytes was elevated; however, the body temperature of the KCASP1Tg mice decreased rapidly, revealing an impaired thermogenesis ability of the AT due to atrophy. Tumor necrosis factor (TNF)-α, IL-1β and interferon (INF)-γ levels were significantly increased in KCASP1Tg mouse ear skin lesions. To investigate the direct effects of these cytokines, BL/6 wild mice were administered intraperitoneal TNF-α, IL-1β and INF-γ injections, which resulted in small adipocytes with abundant stromal cell infiltration, suggesting those cytokines have a synergistic effect on adipocytes. The systemic dermatitis model mice showed atrophy of AT and increased stromal cells. These findings were reproducible by the intraperitoneal administration of inflammatory cytokines whose production was increased in inflamed skin lesions.

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“…Chronic inflammatory skin disease is also associated with metabolic syndrome [5][6][7]. However, the mechanism is under discussion, and the contribution of AT is still unclear.…”

Section: Introductionmentioning

confidence: 99%

Systemic Dermatitis Model Mice Exhibit Atrophy of Visceral Adipose Tissue and Increase Stromal Cells via Skin-Derived Inflammatory Cytokines

Mizutani

Shirakami

Ichishi

et al. 2020

IJMS

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“…Because subcutaneous white adipose tissue is juxtaposed to skin, it may play a role in whole-body communication of skin-derived factors. Subcutaneous fat is considered the safest depot to store fat because the white adipocytes of subcutaneous fat have greater capacity to “beige” compared to visceral or epididymal adipose depots [ 46 ]. As a result, subcutaneous fat can contribute to increased energy expenditure and decreased risk of developing insulin resistance and diabetes [ 46 ].…”

Section: Subcutaneous Adipose Tissuementioning

confidence: 99%

“…Subcutaneous fat is considered the safest depot to store fat because the white adipocytes of subcutaneous fat have greater capacity to “beige” compared to visceral or epididymal adipose depots [ 46 ]. As a result, subcutaneous fat can contribute to increased energy expenditure and decreased risk of developing insulin resistance and diabetes [ 46 ]. However, if subcutaneous white adipose tissue is exposed to inflammatory stimuli, its capacity to beige and respond to insulin is decreased [ 47 ].…”

Section: Subcutaneous Adipose Tissuementioning

confidence: 99%

A Discussion on the Relationship between Skin Lipid Metabolism and Whole-Body Glucose and Lipid Metabolism: Systematic Review

Dumas

Ntambi

2018

J cell signal

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The obesity epidemic is a costly public health crisis that is not improving. In addition to the stigma and discomfort associated with carrying extra weight (at the expense of range of movement), obesity also goes hand-in-hand with co-morbidities like fatty liver disease, diabetes, cardiovascular disease, and increased risk of some forms of cancer. Currently there are no long-lasting treatments for obesity other than diet and exercise, which are not feasible for many populations that may not be equipped with the resources and/or support needed to lead a healthy lifestyle. Although there have been some pharmacological breakthroughs for treating obesity, each FDA-approved drug comes with unpleasant side-effects that make adherence unlikely. As a result, alternate approaches are necessary. In this review, we outline the relationship between skin lipid metabolism and whole-body glucose and lipid metabolism. Specifically, by summarizing studies that employed mice that were genetically modified to interrupt lipid metabolism in the skin. As a result, we propose that skin might be an overlooked, but viable target for combating obesity.

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“…The mechanisms underlying the effects of skin inflammation on whole-body metabolism remain undetermined; however, the skin secretome may play a role. The skin secretes a wide range of proteins, lipids and small molecules [ 3 , [11] , [12] , [13] , [14] , [15] , [16] ] with potential paracrine and endocrine effects. Many skin-derived factors, such as cytokines and glucocorticoids, have established metabolic functions, and altered expression and secretion of such factors would be predicted to exert metabolic effects [ 14 , [18] , [19] , [20] , [21] , [22] ].…”

Section: Introductionmentioning

confidence: 99%

“…The skin is located adjacent to subcutaneous adipose tissue (sAT). sAT dysfunction plays a key role in the development of insulin resistance and T2D [ 15 , [25] , [26] , [27] , [28] ]. sAT is the largest and safest lipid storage depot in the body [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Psoriatic skin inflammation induces a pre-diabetic phenotype via the endocrine actions of skin secretome

Evans

Sayers

Kodji

et al. 2020

Molecular Metabolism

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Objective Psoriasis is a chronic inflammatory skin disease that is thought to affect ∼2% of the global population. Psoriasis has been associated with ∼30% increased risk of developing type 2 diabetes (T2D), with numerous studies reporting that psoriasis is an independent risk-factor for T2D, separate from underlying obesity. Separately, studies of skin-specific transgenic mice have reported altered whole-body glucose homeostasis in these models. These studies imply a direct role for skin inflammation and dysfunction in mediating the onset of T2D in psoriasis patients, potentially via the endocrine effects of the skin secretome on key metabolic tissues. We used a combination of in vivo and ex vivo mouse models and ex vivo human imiquimod (IMQ) models to investigate the effects of psoriasis-mediated changes in the skin secretome on whole-body metabolic function. Methods To induce psoriatic skin inflammation, mice were topically administered 75 mg of 5% IMQ cream (or Vaseline control) to a shaved dorsal region for 4 consecutive days. On day 5, mice were fasted for glucose and insulin tolerance testing, or sacrificed in the fed state with blood and tissues collected for analysis. To determine effects of the skin secretome, mouse skin was collected at day 5 from IMQ mice and cultured for 24 h. Conditioned media (CM) was collected and used 1:1 with fresh media to treat mouse explant subcutaneous adipose tissue (sAT) and isolated pancreatic islets. For human CM experiments, human skin was exposed to 5% IMQ cream for 20 min, ex vivo , to induce a psoriatic phenotype, then cultured for 24 h. CM was collected, combined 1:1 with fresh media and used to treat human sAT ex vivo . Markers of tissue inflammation and metabolic function were determined by qPCR. Beta cell function in isolated islets was measured by dynamic insulin secretion. Beta-cell proliferation was determined by measurement of Ki67 immunofluorescence histochemistry and BrDU uptake, whilst islet apoptosis was assessed by caspase 3/7 activity. All data is expressed as mean ± SEM. Results Topical treatment with IMQ induced a psoriatic-like phenotype in mouse skin, evidenced by thickening, erythema and inflammation of the skin. Topical IMQ treatment induced inflammation and signs of metabolic dysfunction in sub-cutaneous and epidydimal adipose tissue, liver, skeletal muscle and gut tissue. However, consistent with islet compensation and a pre-diabetic phenotype, IMQ mice displayed improved glucose tolerance, increased insulin and c-peptide response to glucose, and increased beta cell proliferation. Treatment of sAT with psoriatic mouse or human skin-CM replicated the in vivo phenotype, leading to increased inflammation and metabolic dysfunction in mouse and human sAT. Treatment of pancreatic islets with psoriatic mouse skin-CM in...

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Can the skin make you fat? A role for the skin in regulating adipose tissue function and whole-body glucose and lipid homeostasis

Cited by 11 publications

References 68 publications

Systemic Dermatitis Model Mice Exhibit Atrophy of Visceral Adipose Tissue and Increase Stromal Cells via Skin-Derived Inflammatory Cytokines

Systemic Dermatitis Model Mice Exhibit Atrophy of Visceral Adipose Tissue and Increase Stromal Cells via Skin-Derived Inflammatory Cytokines

A Discussion on the Relationship between Skin Lipid Metabolism and Whole-Body Glucose and Lipid Metabolism: Systematic Review

Psoriatic skin inflammation induces a pre-diabetic phenotype via the endocrine actions of skin secretome

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