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Published in final edited form as: Bioessays. 2021 Nov 12;44(1):e2100207. doi: 10.1002/bies.202100207

Skin Aging: Dermal Adipocytes Metabolically Reprogram Dermal Fibroblasts

Enhanced fatty acid oxidation and reduced glycolysis in aging skin fibroblasts

Ilja L Kruglikov 1, Zhuzhen Zhang 2, Philipp E Scherer 2,3,*
PMCID: PMC8688300  NIHMSID: NIHMS1752409  PMID: 34766637

Abstract

Emerging data connects the aging process in dermal fibroblasts with metabolic reprogramming, provided by enhanced fatty acid oxidation and reduced glycolysis. This switch may be caused by a significant expansion of the dermal white adipose tissue (dWAT) layer in aged, hair-covered skin. Dermal adipocytes cycle through de-differentiation and re-differentiation. As a result, there is a strongly enhanced release of free fatty acids into the extracellular space during the de-differentiation of dermal adipocytes in the catagen phase of the hair follicle cycle. Both caveolin-1 and adiponectin are critical factors influencing these processes. Controlling the expression levels of these two factors also offers the ability to manipulate the metabolic preferences of the different cell types within the microenvironment of the skin, including dermal fibroblasts. Differential expression of adiponectin and caveolin-1 in the various cell types may also be responsible for the cellular metabolic heterogeneity within the cells of the skin.

Keywords: aging, dermal adipose tissue, glycolysis, oxidative phosphorylation, adiponectin, caveolin, CD36

Graphical Abstract

graphic file with name nihms-1752409-f0001.jpg

Metabolic reprogramming of dermal fibroblasts in skin aging. Dermal fibroblasts show enhanced fatty acid oxidation and reduced glycolysis with skin aging. Aged dermal fibroblasts display a strong reduction in extracellular matrix production. Factors released by dermal adipose tissue modulate metabolic programing of dermal fibroblasts.

Introduction

Synthetically active young fibroblasts have a distinct glycolytic phenotype and choose to process fewer free fatty acids (FFAs) and amino acids. These metabolic preferences are observed in a number of different tissues and appear to be of general biological relevance..[1–3]Typically, fibroblasts demonstrate a reduction of synthetic activity in aging that is often connected to the development of cellular senescence, characterized by a special senescence-associated secretory phenotype (SASP). Senescent cells demonstrate high metabolic activity, which is, however, substrate dependent. The existence of a glycolytic phenotype antagonizes entry into senescence,[4] whereas fatty acid synthase (FASN) levels are increased during induction of senescence in primary human fibroblasts. Inhibition of FASN or its knockdown leads to an inhibition of entry into senescence.[5] On the other hand, increased glycolysis and redox homeostasis were found in vitro in senescent cells with decreased fatty acid oxidation.[5] Thus, metabolic substrates can differentially influence both the entry into senescence and the behavior of established senescent cells.

Glucose is an important, but not unique, substrate that can be metabolically processed by dermal fibroblasts. These cells can quickly adapt to substrate insufficiency and can effectively switch their metabolism to utilize amino acids, FFAs as well as their breakdown products. Aged fibroblasts in vitro are characterized by increased levels of lipids and higher expression of FA synthase than young fibroblasts.[6] Moreover, dermal fibroblasts demonstrate adipogenic potential by incubation in adipogenic differentiation medium, leading to a dose-dependent lipid accumulation and triglyceride formation as well as to the expression of adipocyte markers in these cells. [7] A very recent report indicated that puerarin (an isoflavonoid found in the plant Pueraria lobate) can prevent the development of an aging phenotype in human dermal fibroblasts, significantly decreasing the ratio of senescent-associated beta-galactosidase-positive cells.[8] This can be connected to its ability to enhance FA oxidation and thus to prevent the accumulation of intracellular lipids. Remarkably, senescent cells of different types (including human primary fibroblasts) produce FAs de novo and are characterized by significantly increased levels of FA synthase activity at the initial stages of transition to senescence.[9] In the presence of exogenous palmitate at physiological concentrations, these cells primarily consume the available FFAs from the medium and synthesize just about 10% of required FAs de novo.[10] This means that the aging fibroblasts not only synthetize, but also effectively consume exogenous FFAs.

Consumed metabolic substrates define not only the cellular energetic homeostasis, but can also influence the cellular phenotype.[2,11] Downregulation of FA oxidation with simultaneous upregulation of glycolysis leads enhanced overall synthetic activity in dermal fibroblasts, whereas activation of the peroxisome-activated receptor gamma (PPARγ) that leads to a stimulation of FA oxidation, generates an overall catabolic phenotype in these cells, including the typical internalization and lysosomal degradation of extracellular matrix (ECM) components.[2] Accordingly, suppression of glycolysis downregulates ECM production both at the RNA and protein level, even under conditions of intact FA oxidation and physiological PPARγ levels.[2] This raises the question as to whether reduced expression of ECM typically observed in aging skin is reflecting reduced glycolytic processes and enhanced FA oxidation in dermal fibroblasts, due to interactions with adjacent age-modified adipose tissue.

Dermal adipocytes as a source for FFAs in the skin

The presence of FFAs in the extracellular milieu was traditionally connected to their transport from circulation as well as to their presence in sebum. However, FFA levels can be also increased in the cells which are located in a close proximity to adipocytes.[12] Such a release of FFAs by adipocytes is not just a passive process; tumor cells, for instance, can activate FFA release from adjacent adipocytes, and this activation can increase FFA uptake and oxidation.[13,14]

Recently, we have reported that dermal adipocytes located in the superficial layer of the subcutis as well as around the hair follicles (HFs) can release substantial amounts of FFAs, serving as an alternative source for FFAs for adjacent dermal fibroblasts in vivo.[15,16] Whereas the phenotypical evolution of dermal adipocytes with chronological aging has not yet been investigated in detail to date, we have shown in a murine model that these cells undergo quick phenotypical transformations tightly connected to the phases of HF cycle.[15] The majority of the murine dermal adipocytes undergo a cyclical de-differentiation with adipocytes morphing into adipocyte-derived preadipocytes in the catagen phase and a re-differentiation back into mature adipocytes in the anagen phase of the HF cycle.[15,17] Remarkably, under proper conditions, preadipocytes appearing in the catagen can leave these cyclic transformations and be trans-differentiated into synthetically active myofibroblasts, inducing pro-fibrotic skin conditions when prompted to do so. Morphologically, these phenotypical modifications are connected to significant temporal oscillations of the dWAT volume: a strong reduction of this volume in the catagen is accompanied by a quick local release of FFAs into the extracellular space, whereas a restitution of the dWAT volume in the anagen is connected to the induction of lipogenesis in these cells.[15,16,18] Such processes lead to specific spatiotemporal distribution of FFAs in the skin, periodically changing the availability of these metabolites for adjacent dermal fibroblasts and other kinds of skin cells.

Concerning slow aging processes in the skin and adjacent adipose tissue, there are three distinct morphological modifications in aging: a moderate reduction of dermal thickness, a significant expansion of dermal white adipose tissue (dWAT) located at the interface between the dermis-subcutis, and a pronounced decrease of subcutaneous white adipose tissue (sWAT).[17,19–21] Reduction of the dermal thickness and the simultaneous expansion of dWAT should be considered as a reciprocal processes, since the dermis and dWAT present two different layers of the same anatomical structure.[17,19] Remarkably, dWAT and sWAT layers demonstrate opposite behaviors in chronological aging, which may be, among other reasons, connected to the fact that the dermal adipocytes that constitute dWAT are critically involved in skin homeostasis and have a very distinct phenotype that significantly differs from the classical lipid-laden white adipocytes.[15,19]

Very recently, it was reported that subcutaneous aging is caused by a dramatic reduction of precursor cells in sWAT and progressive appearance of a special subpopulation of cells, referred to as aging-dependent regulatory cells (ARC).[22] These cells bear adipose progenitor markers, but are unable to morph into mature adipocytes. The transcription factor PU.1 (also known as SPI1) is critically involved in the development of these cells. These preadipocytes that ectopically express PU.1 are also able to secrete chemokines that inhibit proliferation and differentiation of neighboring cells in vitro,[22] thereby constituting an example of “paracrine senescence”. Indeed, whereas senescence was for a long time considered a pure autocrine process, there is also growing evidence that it can be transmitted to neighboring non-senescent cells through a paracrine mechanism.[23] Such ARC seem to be much less prevalent, or even absent, in aging dWAT. This can explain in part why dWAT and sWAT exhibit opposite morphological changes in aging. However, the specific involvement of these cells in dWAT deserves further study.

Aged dermal fibroblasts have distinct pro-adipogenic traits

Ablation of dermal adipocytes in murine model in vivo demonstrated a significant reduction of dermal fibroblast genes related to FFA oxidation.[16] This supports the notion that dermal adipocytes can supply FFAs as metabolites to adjacent dermal fibroblasts. We can therefore assume that the significant expansion of dWAT in aging causes a differential release of FFAs into the extracellular space, which in turn can modulate the FFA uptake and oxidation in reticular fibroblasts.

Metabolically-induced reprogramming can influence cellular phenotype of fibroblasts.[2,11] This raises the important question as to whether dermal fibroblasts demonstrate phenotypical changes in aging. Aged fibroblasts indeed express about 1,000 transcripts, which differentiates them from the corresponding gene spectrum in their younger counterparts.[20] Remarkably, these cells demonstrate not just a reduced expression of different ECM genes, but also an upregulation of genes involved in inflammation, adipogenic differentiation and lipid metabolism. This means that the aging of dermal fibroblasts is generally associated with a reduction of typical fibroblast markers and the acquisition of pro-adipogenic traits in these cells.[20] Since epigenetics and cellular metabolism strongly interplay with each other,[24] metabolic reprogramming of dermal fibroblasts should influence their aging.

Receptor CD36 in metabolic reprogramming

CD36 is a multi-ligand scavenger receptor that serves as a FFA transporter with a high affinity for long-chain FFAs, phospholipids as well as for high- and low-density lipoproteins.[25] This receptor is therefore crucially involved in the metabolic behavior of fibroblasts. Remarkably, reticular fibroblasts express much higher levels of CD36 than papillary fibroblasts, which can point to a lower ability of these papillary fibroblasts to process FFAs.[26] A reduction of the papillary dermis is considered an important weak link, substantially influencing the mechanical properties of the skin.[27] Another weak link in skin aging is the deterioration of the dermal-hypodermal junction (DHJ). [27] Recent findings suggest that dermal fibroblasts located at DHJ have a phenotype remarkably distinct from papillary and reticular fibroblasts; among other characteristics, these cells have very high expression levels of CD36,[28] which allows them to increase the available supply of FFAs.

The senescent cells not just cease to proliferate, but they show also an altered metabolic activity, including substantial changes in the overall lipid metabolism and the accumulation of long chain FFAs.[29] CD36 expression continuously increases with aging and rapidly rises in different types of cells, including various lines of fibroblasts, in response to replicative, oncogenic, and chemical senescent stimuli.[30] Consequently, a modification of lipid metabolism should be causally involved in the development of replicative senescence.[31,32]

FFA transport across the plasma membrane is achieved through CD36; for this, CD36 must be palmitoylated to be localized to the plasma membrane.[33] While palmitoylated CD36 captures FFAs on the plasma membrane, de-palmitoylated CD36 is needed to initiate endocytosis.[33] Hence, a proper absorption of FFAs by fibroblasts demands a strict regulation between the processes of palmitoylation and de-palmitoylation of CD36. Indeed, suppression of acyl-protein thiosterase 1 (APT1) with palmostatin B (thereby inhibiting de-palmitoylation of CD36) strongly reduces the endocytic uptake of FFAs.[33] Thus, the metabolic phenotype of dermal fibroblasts is not only dependent on the availability of FFAs that are necessary for their consumption by dermal fibroblasts, but also on the presence of CD36 receptors in the plasma membranes of these cells, as well as on the proper spatiotemporal dynamics of the palmitoylation and de-palmitoylation of CD36 with the ensuing targeting to the plasma membrane. This raises the issue that the expression profile of APT1 in aged fibroblasts may be interesting to look at, an aspect which we believe has not yet been addressed.

CAV1 in metabolic reprogramming of dermal fibroblasts

Other interesting sites of regulation for FFA uptake are plasma membrane invaginations known as caveolae. CD36 receptors partition into caveolae and need the protein caveolin-1 (CAV1) in the plasma membrane to implement FFA uptake and transport.[34,35] A molecular analysis reveals that the interactions of upregulated CD36 with its ligand Aβ is sufficient to induce the senescent state in fibroblasts.[30] This senescent state is associated with an increased level of CAV1 observed in aged fibroblasts.[17,36] This should provide the necessary conditions for the CD36-mediated, caveolar based endocytosis of FAAs. In line with this, a depletion of CAV1 blocks the CD36-mediated endocytosis and prevents transport of FFAs into cells.[33]

Whereas deficiency of CAV1 is recognized as an important hallmark of inflammatory and hyperproliferative skin conditions, overexpression of CAV1 is connected to senescent conditions, such as skin aging or non-healing wounds. [17,18,36–40] There are some indications that CAV1 levels are inversely related to a glycolytic phenotype.[41] Correspondingly, CAV1 deficiency increases carbohydrate metabolism in mice and prevents the metabolic switch from glycolysis to FFA oxidation.[41] Moreover, CAV1 modulates FFA metabolism and its induced deficiency causes a switch from FA oxidation to glycolysis in an array of cell types.[41] Expression of CAV1 can also directly influence the uptake of FFAs, for example, affecting the association of FA binding proteins with caveolae.[42] The upregulation of CAV1 was also associated with enhanced transcytosis of low density lipoproteins (LDL) induced by pro-inflammatory factors.[43] Interestingly, LDL transcytosis can also be enhanced by increased glucose levels, leading to the suppression of the autophagic degradation of CAV1.[44] From here, we can infer that senescent cells have a higher affinity to FFAs. This is consistent with earlier reports that found that direct inhibition of glycolytic enzymes can induce cellular senescence [45] and that a glycolytic phenotype antagonizes entry into senescence.[4] Seemingly contradictive to this, senescent human diploid fibroblasts demonstrate increased consumption of glucose but decreased aerobic glycolysis,[46] which suggests that these cells may process the consumed glucose for non-energetic purposes.

Overexpression of CAV1 in dermal fibroblasts enhances the TGFβ-ALK1-SMAD1 signaling pathway. CAV1 expression is necessary and sufficient for SMAD1 phosphorylation,[47] implicating it in an array of different metabolic processes. TGFβ1 inhibits PPARγ expression and thus represses the lipogenic and activates the myogenic program in human lung fibroblasts.[48] This can cause the differentiation of lung fibroblasts into myofibroblasts, leading to the development of lung fibrosis. The appearance of synthetically active myofibroblasts in the tissue is accompanied by a remarkable metabolic reprogramming, causing the induction of glycolysis and the accumulation of lactate.[48] Among others, this process is controlled by sonic hedgehog,[49] which is known as a strong anti-aging factor.[50] Remarkably, the synthetic activity of fibroblasts and the appearance of myofibroblasts in the tissue are connected to the loss of CAV1 in these cells, and such a loss was considered as a sufficient condition for the appearance of a synthetically active cellular phenotype.[51] Of note, suppression of CAV1 leads not only to the upregulation of myofibroblast markers, but also to the overexpression of various glycolytic enzymes.[51]

It should be also mentioned that CAV1 is co-localized and physically interacts with CD26, a receptor containing dipeptidyl peptidase 4 (DPP4) activity.[52] DPP4 is involved in ECM homeostasis, regulating the process of lipolysis in dermal adipocytes. Exposure to DDP4 inhibitors can prevent fibrosis or accelerate its resolution.[53] Since CAV1 was shown to be a target for DPP4 inhibitors,[52] this connection can mechanistically explain the established role of low CAV1 expression in fibrotic diseases, among others in hypertrophic scars and keloids.[38]

Adiponectin and its connection to CAV1

Adiponectin (APN) is one of the most important adipokines produced by mature adipocytes and serves as an important master regulator of metabolism. APN regulates glucose and lipid metabolism, is effectively suppressing tissue inflammation and fibrosis[54] and exerts overall an essential role in regulating health- and lifespan.[55] In vitro studies demonstrate that APN can reduce expression of IL-6 in human keratinocytes and increase production of hyaluronan and collagen in dermal fibroblasts.[7,56]

Whereas the main research concerning the relationship between APN and different skin conditions focused on correlations of APN levels in serum, there is growing evidence that the APN levels in the local skin microenvironment should be of primary importance in skin inflammatory and hyperproliferative conditions, as well as in skin aging. APN levels in skin correlate with fat mass,[7] but it should be noted that dWAT vs. sWAT demonstrates an expansion vs. a reduction in aging, and thus, these two types of adipose tissue can differentially influence the skin APN levels.[17,21] In this regard, APN expression in murine skin markedly decreases with aging, correlating with local reduction of hyaluronan content.[57] Remarkably, the application of exogenous APN increases the adhesive strength and elastic modulus of dermal fibroblasts irradiated with UVA,[7] thus contributing to a distinct anti-aging phenotype.

The APN levels in the skin as well as in adjacent adipose tissue are significantly reduced in human psoriatic plaques as well as in a murine model of psoriasiform skin inflammation.[58] APN is also significantly reduced in systemic sclerosis skin biopsies, and this reduction strongly correlates with the attrition of the dWAT layer adjacent to fibrotic areas.[59] Expression levels of APN and its receptors (AdipoRs) are also decreased in keloids compared to their values in normal skin,[60] supporting the idea that such a reduction in APN must be typical for hyperproliferative skin conditions. APN deficiency is typical seen in sensitive skin.[61] Further, wounds demonstrate reduced APN expression, and wound closure is significantly delayed in APN-deficient mice, whereas topical application of APN ameliorates the healing.[62]

There are remarkable correlations in expression of APN and CAV1. In human endothelial cells, AdipoR1 interacts with CAV1, producing an AdipoR1/CAV1 complex that is critically involved in APN signaling under physiological conditions.[63] As it was shown in HUVEC cells, downregulation of CAV1 leads to dissociation of AdipoR1/CAV1 complex, impairing APN effects, whereas knock-in of CAV1 in CAV1 knock-down cells restores APN signaling.[63] On the other hand, induced overexpression of APN correlates with increased expression of CAV1 in adipocytes.[64]

Although inflammatory and hyperproliferative skin conditions are characterized by reduced expression of both APN and CAV1, there are substantial differences found between the two in skin aging: whereas aged cells are characterized by enhanced levels of CAV1,[17,40] APN expression in murine skin significantly decreases with aging.[57] It is not understood why this differential regulation is observed during aging, but this certainly sets the stage for further research in that area.

Nuclear receptors - some parallels with adipose and muscle tissues

Signaling pathways controlling metabolic homeostasis are connected to nuclear receptors and their co-regulators operating as transcriptional factors.[65] One of these receptors is the nuclear receptor interacting protein 1 (NRIP1), also known as RIP140, which is highly expressed in different tissues, including WAT and skeletal muscles. Whereas NRIP1 is normally localized in the nucleus, phosphorylation of NRIP1 leads to its nuclear export and localization in the cytoplasm. In the cytoplasm, this factor inhibits glucose uptake and metabolism and enhances lipolysis through interaction with perilipin.[65] NRIP1 can bind to and repress some other nuclear receptors (among others, the PPARs), which are key regulators of lipid metabolism.[65] Depletion of NRIP1 was shown to extend longevity in mice and to delay entry into senescence of mouse embryonic fibroblasts.[66] Recently, it was reported that depletion of NRIP1 also delays skin aging, reducing expression of genes associated with senescence and inflammation in adipose-derived mesenchymal stem cells.[67] This provided a significant improvement of some important skin aging hallmarks, including an increase of dermal and sWAT thickness.

NRIP1 regulates the ratio between type I (oxidative) and type II (glycolytic) fibers in the muscles – an elevation of NRIP1 expression results in an increased proportion of type II fibers.[66] This means that high expression of NRIP1 can shift metabolism in muscle fibers to the glycolytic pathway. NRIP1 is also highly expressed in adipose tissue and regulates its metabolism: whereas NRIP1 silencing in cultured adipocytes increased mitochondrial oxygen consumption, overexpression of NRIP1 suppressed oxidative metabolism.[68] Modulation of NRIP1 was sufficient to switch the metabolic pathway in these cells from oxidative phosphorylation to glycolysis. Remarkably, a similar correlation was revealed for the mesodermal transcription factor T-box (Tbx15): preadipocytes and mature adipocytes expressing Tbx15 at low levels were found to be highly oxidative, whereas high Tbx15 levels prompt a more glycolytic phenotype; moreover, enhanced expression of Tbx15 was sufficient to reduce oxidative and increase glycolytic pathways in these cells.[69] A very similar metabolic prevalence was observed in muscle, where Tbx15 was highly and specifically expressed in glycolytic fibers, and the ablation of Tbx15 effectively decreased the number of these fibers.[70] These comparable effects of NRIP1 and Tbx15 can be explained by the fact that both NRIP1 and Tbx15 interact with the Akt/PKB signaling pathway, a key regulatory pathway of glucose metabolism. For example, NRIP1’s cytoplasmic location prompts an interaction with the Akt substrate AS160, preventing its phosphorylation by Akt and thus reducing GLUT4 trafficking, causing reduced glucose uptake.[71]

Such close parallels between NRIP1- and Tbx15-induced effects on metabolic regulation of muscle and adipose tissue points to the existence of metabolically different subpopulations of cells in these tissues, characterized by glycolytic or oxidative metabolic prevalence, respectively. Whereas such metabolically heterogeneous subpopulations of dermal fibroblasts were not described so far, their existence and involvement in skin aging may be inferred. Moreover, taking into account the mechanism of paracrine senescence, providing transmission of senescence to neighboring cells,[23] such metabolically distinct subpopulations of cells should appear in the form of spatially restricted clusters, leading to a metabolically mosaic skin structure.

Conclusions

Aging dermal fibroblasts undergo metabolic reprogramming, characterized by enhanced FA oxidation and reduced glycolysis. There is a significant expansion of the dWAT layer in the aged, hair-covered skin. Dermal adipocytes in the catagen phase of the HF cycle de-differentiate and demonstrate an enhanced release of FFAs into the extracellular space. Whereas in young subjects, such a release is normally spatially limited to single HFs, expansion of dWAT in aging should provide an extension of this effect to the intra-follicular space. In murine models, such a release of FFAs is temporally limited to the relatively short catagen phase of the HF cycle. In humans, HFs lacks spatial coordination in cycling. This must provide permanently increased and area-covering levels of released FFAs, and thus conditions are established for a permanent metabolic impact of dermal adipocytes on adjacent dermal fibroblasts. Selective modification of dWAT without a reduction of the subcutaneous layer or a specific suppression of lipolysis in dWAT may be an important target in skin rejuvenation.

Acknowledgments

PES is supported by NIH grants R01-DK55758, R01-DK099110, R01-DK127274, RC2-DK118620 and P01-AG051459.

Conflict of interest

ILK is the managing partner of Wellcomet GmbH. Wellcomet GmbH provided support in the form of salaries for ILK, but did not have any additional role in decision to publish or preparation of the manuscript. The commercial affiliation of ILK with Wellcomet GmbH does not alter the adherence to all journal policies on sharing data and materials. PES and ZZ declare no conflict of interest.

Abbreviations:

dWAT

dermal white adipose tissue

CAV-1

caveolin-1

DPP4

dipeptidyl peptidase 4

ECM

extracellular matrix

FFA

free fatty acid

HF

hair follicle

PPARγ

peroxisome-activated receptor gamma

sWAT

subcutaneous white adipose tissue

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