The human body is in a constant state of change due to both intrinsic and extrinsic factors. In relation, the uneven distribution of fat at all ages leads to physical appearance-related consumer concerns. As such, the market is replete with curative-themed cellulite and excess body fat-reduction products and services, which address sagging eyelids, drooping cheeks, double chins, fatty necks and flabby arms and thighs.
Dietary supplements, exercise videos, prescription medications and surgical treatments are mainly curative routes to mask these problems, not prevent them.
Marketers have mostly ignored the need to focus on prevention, to forestall the problems caused by the unsightly distribution of adipose tissue. Ideally, in a preventive mode, excess fat production would be inhibited where fat is undesired on the body and accelerated on the body where it is desired. In a fully curative mode, the excess fat from one part of the body may be transported to another body part requiring lipo-filling. This redirection of fat from excess areas of the arms, thighs, hips, abdomen, chin and eyelids to plump skin and reduce wrinkles or augment lips and breasts could become a cosmetic reality, such as through gene modulation.
Imagine if lipogenesis/lipolysis and/or adipogenesis/adipolysis could be genetically redirected by lipo-transmogrifying cosmetics. While the industry may not be fully there yet, the present article reviews novel approaches to anti-cellulite effects and nature-based cosmetic actives on the path to preventive and curative approaches for body sculpting.
The Science of Fat
The distribution of fat in the body is related to the regulation of energy intake, expenditure and storage in the body. Excess consumed energy is converted into triglycerides and stored in adipocytes as lipid droplets. Energy-rich nutrition initiates the activation of inflammatory processes in metabolically active sites such as adipose tissue, the liver and immune cells, which results a sharp increase in circulating levels of pro-inflammatory cytokines, adipokines and other inflammatory markers.1-8
This fat-rich state is thus characterized by systemic inflammation as a result of increased adipocytes as well as fat resident- and recruited-macrophage activity. Excess fat storage also increases the expression of leptin and other cytokines and some macrophage and inflammatory markers. It decreases adiponectin expression in adipose tissue as well.1-8
Anti-cellulite ingredients mainly act by increasing microcirculation flow, reducing lipogenesis and promoting lipolysis, restoring the normal structure of the dermis and subcutaneous tissue and scavenging free radicals or preventing their formation.9 For example, the inhibition of acetyl-CoA carboxylase both inhibits fatty acid synthesis and stimulates fatty acid oxidation. Additionally, the role of fatty acid-binding proteins, a family of lipid chaperones, has gained increasing scientific interest.1-8 A large amount of information regarding biochemical mechanisms for adipose production and storage is available, some of which is summarized in Figure 1.
Adipose-affecting active agents belong to a variety of chemical classes including saponins, polysaccharides, alkaloids, polyphenols and others. Their chemical structures range from ubiquitous to exotic;10-13 select examples are illustrated in Figure 2 and listed in Table 1.14-49
Among the most established and well-known anti-cellulite ingredients is caffeine and its analogs, which have found applications in a number of topical and nutritional supplement preparations. Commercial preparations based on caffeine have been presented in a recent article.50 Topicals including caffeine typically contain 3% as the active anti-cellulite compound. The selection of proper delivery systems can assist in the skin penetration of such agents.
Caffeine has been shown to prevent the excessive accumulation of fat in cells and stimulate the degradation of fats during lipolysis by inhibiting phosphodiesterase activity. In addition, it increases intracellular levels of cAMP, which is used for intracellular signal transduction. It also increases the microcirculation of blood and thus stimulates the growth of hair through the inhibition of 5-α-reductase activity.51
Combinations of caffeine with other cellulite-reducing agents also have been developed; for example, tetrahydroxypropyl ethylenediamine, carnitine, forskolin, ruscogenin and retinol.52, 53 Combinations using different ingredient types having different mechanisms typically show greater efficacy; especially, again, when they are combined with the right delivery system.
As an aside, it is interesting to note tetrahydroxypropyl ethylenediamine also exhibits anti-aging effects due to the morphological changes it induces in epidermal keratinocytes, which tighten skin.54 As far as delivering caffeine, among the latest novel delivery systems is caffeine loaded onto solid lipid nano-particles, which has been shown to increase caffeine accumulation in skin.55-57
Capsaicin has long been recognized for its anti-obesity and adipose-modulating benefits. Recent work has revealed transient receptor potential vanilloid 1 (TRPV1) channels take part in weight loss by enhancing intracellular Ca2+ levels. In addition, TRPV1 activation by dietary capsaicin improves visceral fat remodeling through the up-regulation of Cx43.58, 59 Topical applications of capsaicin have been limited due to its strong skin and mucous irritation properties and pungent taste; however, capsinoids have potential to inhibit fat accumulation in adipocytes.60
Circadian Rhythm Modulation
Metabolic rhythm is under the control of endogenous circadian clocks and becoming a new area of research for the management of adipose tissue. Circadian rhythms are controlled by specific proteins known as: Circadian Locomotor Output Cycles Kaput (CLOCK), Brain and Muscle ARNTL-like 1 (BMAL1), Period (PER), Human Timeless (hTIM), cryptochrome (CRY), RevERB-α and Nocturnin (Noc).61, 62
Circadian modulation by CLOCK proteins is of interest in the management of dietary lipid
Noc is a rhythmic gene encoding a deadenylase enzyme thought to be involved in the removal of polyA tails from mRNAs.65-69 Although most Noc-related studies have been conducted in mice, recent evidence in Chinese human subjects suggests circadian clock and adipose function go hand-in-hand and genetic variations in the Noc gene are associated with body mass index.70-73
In another study, unlike in mice, circadian gene oscillations in human adipose tissue appear to be independent of body mass index or diabetes status, suggesting circadian mechanistic variations occurs across species.74 In relation, an enzyme-linked immunosorbent assay using a specific antibody against human nocturnin protein has been used to screen microbiological extracts for their efficacy in modulating human nocturnin.75, 76 This led to the development of an active77 derived from plankton microorganisms of Fuente de Piedra, Spain, which targets the expression of the circadian protein nocturnin in adipocytes.
Bidirectional Lipid Flow
As stated, the management of adipose tissue and triglycerides such that they could be reduced in some body sites and enhanced in others would be the epitome of scientific achievement. The plasma membrane proteins aquaporin-7 (AQP7) and aquaporin-10 (AQP10) are known to be expressed in adipose tissue, and their role in glycerol release/uptake in adipocytes has been correlated78, 79 with triglyceride content in adipocytes.
While AQP7 is present in both the adipocyte and capillary plasma membranes of human adipose tissue, AQP10 is expressed exclusively in the adipocytes.78, 79 Thus, the management of AQP7 and AQP10 could, in theory, permit either the accumulation or depletion of triglyceride or adipose tissue in human body.
An adipocytic phenotype test has been developed to screen plant extracts for their adipocyte-modulating activity.80 Of the materials tested thus far, Dioscorea opposita (wild yam root), Theobroma cacao (cocoa bean), Aesculus hippocastanum (horse chestnut tree) seed and bark and Solanum lycopersicum D. opposita (tomato) appear to induce a dose-dependent glycerol release.
Manipulating the size of adipocytes by controlly autonomic nerves in the adipose tissue is another way to direct the flow of triglycerides. In one study, L-ornithine ingestion was found to stimulate afferent vagal nerves and activate the central nervous system, leading to the reduction of adipose tissue.81 In relation, a topical delivery system for L-ornithine was reported to increase the size of adipose cells,82 whereas a combination of L-arginine and conjugated linoleic acid was found to modulate adipose tissue metabolism by separate mechanisms, in turn reducing retroperitoneal fat mass and increasing lean body mass.83
Nicotinamide N-methyltransferase (Nnmt) has been reported84 as the most strongly reciprocally regulated gene in white adipose tissue (Wat); note adipocytes are grouped as two types: brown and white. Brown adipocytes are mitochondria-rich and use energy, whereas white adipocytes store energy. Nnmt methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor. Nicotinamide is a precursor of NAD(+), an important cofactor linking cellular redox states with energy metabolism. Nmnt expression is increased in the Wat and livers of obese and diabetic mice. On the other hand, Nnmt down-regulation in Wat and the liver protects against diet-induced obesity by augmenting cellular energy expenditure.
This up- or down-regulation of Nnmt could lead to better management of triglyceride accumulation via energy conservation or triglyceride depletion via energy expenditure in adipose tissue.84
As described, excess energy consumption is converted into triglyceride, which is stored in adipocytes as lipid droplets. This process is known as Lipid Droplet Accumulation (LDA), for which the biochemical steps involved are shown in Figure 3.47, 48 Thus, the up-regulation or down-regulation of these biochemical steps could lead to a topical solution of the adipose dilemma—the comprehensive discussion of which is beyond the scope of this article.
As noted, adipocytes are grouped as brown and white and all mammalian cells are known to contain some lipid droplets, but the differentiated white and brown adipocyte cells possess larger-sized lipid droplets in higher numbers. As such, the differentiation process of white adipocytes from precursor cells could be a target for LDA inhibition.
Apart from inhibiting adipogenesis, anti-LDA effects may also be achieved by preventing the adipocyte from accumulating lipid droplets. Energy consumption causes the lipid droplets stored in adipocytes to hydrolyze triglyceride to fatty acids and glycerol via lipolysis. Further, the up-regulation of lipolysis may also be effective in lowering adipocyte lipid droplets.47, 48
Adipophilin, or adipose differentiation-related protein (ADRP), is a 50-kDa protein initially described in adipocytes. It is considered a marker of lipid accumulation and is among the genes up-regulated by modified low-density lipoproteins (LDL). Adipophilin is also associated with intracellular lipid droplets in a variety of cells and tissues storing or synthesizing lipid. Interestingly, the up-regulation of adipophilin expression by modified LDL has been found to promote triglyceride and cholesterol storage, whereas the down-regulation of adipophilin can cause triglyceride movement in the opposite direction.85
Perilipins (Plin) are related proteins and have been reported to limit the interaction of lipases with neutral lipids within the droplets, thereby regulating neutral lipid accumulation and utilization. Five proteins of the Plin family have been characterized as lipid droplet (LD) proteins in adipocytes: Perilipin (Plin1); Adipose Differentiation-related Protein or Perilipin 2 (Plin2); 47 kDa Tail-interacting Protein (Plin3); S3-12 (Plin4); and Myocardial Lipid Droplet Protein (Plin5).
Plin2 has been shown to bind lipids with high affinity, which has been suggested as important for lipid droplet biogenesis and intracellular triacylglycerol accumulation. Plin2 interacts directly with lipids on the surface of lipid droplets, influencing levels of key enzymes and lipids involved in maintaining lipid droplet structure and function.86-89
Finally, Fatty Acid Binding Protein 3 and 7 (FABP3 and FABP7) are both involved in fatty acid uptake. The down-regulation of FABP3 or FABP7 as well as adipophilin has been reported to significantly impair lipid droplet formation.90 A number of plant-based anti-droplet accumulation agents have also been reported (see Table 1).47, 48
Proteasomes, MMPs and Fibroblast Growth Factors
The role of polyunsaturated fatty acids (PUFAs) in lipid metabolism is well-known. Interestingly, however, ω-3 PUFA in particular has been found to induce the degradation of fatty acid synthase through the ubiquitin-proteasome system, which in turn should affect adipose cells. Proteasome inhibition also induces adipophilin while decreasing perilipin expression. This finding warrants further research.91, 92
In relation, cellular hypoxia causes hepatocytes to consume less oxygen by shifting energy production from mitochondrial fatty acid β-oxidation to glycolysis. This results in the activation of hypoxia-inducible factor (HIF) and recent studies suggest both HIF-1α and HIF-2α are involved in lipid accumulation in hepatocytes by reducing PGC-1α mediated fatty acid β-oxidation.93 In fact, one L-ornithine-based composition has been developed to topically increase the size of adipose cells by HIF-1α activation, for skin-plumping effects.82
The expansion of adipose tissue is dependent on adipogenesis, angiogenesis and extracellular matrix remodeling. This involves the differentiation of preadipocytes into mature, lipid-containing adipocytes. Matrix metalloproteinases (MMPs) are known regulators of such processes in adipose tissue. In particular, gelatinase A, or MMP-2, has been found to play a positive role in adipogenesis, opening a new pathway to managing the size of adipose cells: by its up- or down-regulation.94, 95
Fibroblast growth factor 2 (FGF2) also has been reported to display enhanced capacity96 for adipogenesis. FGF2 at concentrations lower than 2 ng/mL enhanced the adipogenesis of human adipose-derived stem cells (hASCs) in vitro, while at concentrations higher than 10 ng/mL, it was able to suppress adipogenesis. This biphasic property of FGF2 could lead to the development of adipogenesis-selective agents.96
Adipose accumulation and associated disorders such as insulin resistance and type 2 diabetes are associated with a metabolically driven, low-grade, chronic inflammatory state known as metaflammation. Inflammatory cytokines as well as lipids and metabolic stress pathways can cause metaflammation, which targets metabolically critical organs and tissues including adipocytes. Within cells, fatty acid-binding proteins (FABPs), a family of lipid chaperones; endoplasmic reticulum (ER) stress; and reactive oxygen species derived from mitochondria all play significant roles in the promotion of metabolically triggered inflammation.
FABPs coordinate lipid trafficking and responses in cells and can reversibly bind to hydrophobic ligands, such as saturated and unsaturated long-chain fatty acids, eicosanoids and other lipids. To date, at least nine different FABP isoforms have been identified, including adipocyte FABP (A-FABP or FABP4) and adipocyte P2 (aP2) isoforms and all are expressed most abundantly in tissues involved in active lipid metabolism.
FABPs have been proposed to facilitate the transport of lipids to specific compartments in the cell, such as the mitochondrion or peroxisome for oxidation; the nucleus for lipid-mediated transcriptional regulation; the endoplasmic reticulum for signaling, trafficking and membrane synthesis; cytoplasmic enzymes for activity regulation; and the cytoplasm for storage as lipid droplets.
FABP4 is one of best-characterized isoforms and is highly expressed in adipocytes. Thus, the enhancement or up-regulation of its transport to the cytoplasm could lead to adipose accumulation, whereas its inhibition could achieve the reverse.97, 98
Lipokines, Stem Cells, Obesogens and Fetuin-A
The activation/induction of fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD-1) is known to increase de novo lipogenesis in adipose tissue. The unsaturated free fatty acid palmitoleate (C16:1n7) has been identified as an adipose tissue-derived lipid hormone, referred to as lipokine, which has been shown to stimulate glucose transport in skeletal muscle.99 In relation, adipose tissue uses lipokines such as palmitoleate to communicate with distant organs to regulate metabolic homeostasis.
Interestingly, the absence of FABP4 in macrophages has been discovered to activate de novo lipogenesis pathways through the LXRα-mediated activation of SCD-1. In a U.S.-based study of 3,630 subjects, high concentrations of circulating cis-isomer palmitoleate, which is primarily produced by the liver in humans, were associated with adiposity, carbohydrate consumption and alcohol use.100, 101 Glucocorticoids are also known to play a role in adiposity, as glucocorticoid receptors mediate the differentiation of adipose tissue. The inhibition of protein phosphatase-5 causes the modulation of the above glucocorticoid action.102
Adipose-derived stem cells (ASC) also are gaining interest since their numbers have been found to increase during adipogenesis. For example, the interferon-inducible protein 202 (P202) is a key regulator of cell proliferation and differentiation, and its levels increase during adipogenesis. This may be due to a role in ASC-faciliated adipogenesis. The inhibition of P202 could therefore modulate adipogenesis via its affect on ASC accumulation.103
In relation, one ingredient from Indian Gentian leaves, Swertia chirata extract, has been found to stimulate the keratinocyte growth factor production in adipose-derived stem cells (ASC) via a cell-to-cell communication between ASC and keratinocytes.104 Indeed, further studies on the role of lipokines and ASC in the management of adipose tissue are warranted.
Recently a class of chemicals called obesogens has been discovered that can directly or indirectly lead to increased fat accumulation and obesity. Obesogens have the potential to disrupt multiple metabolic signaling pathways in a developing organism, resulting in permanent changes in adult physiology. Bisphenol A and phthalates, for example, have been implicated as obesogens although this research is still inconclusive.
Prenatal or perinatal exposure to obesogenic chemicals has been linked to increased fat storage from the beginning of human life, possibly due to altered stem cell compartments preprogrammed toward an adipogenic fate. For example, excess oestrogen or cortisol exposure in the womb or during early life has resulted in an increased susceptibility to obesity later in life.105-110
Finally, adipocyte fetuin-A has been identified as a novel signaling molecule in lipid-induced tissue inflammation. Adipose tissue from obese diabetic patients has shown significantly elevated fetuin-A levels. Macrophage infiltration into adipose tissue and the phenotypic conversion from anti-inflammatory M2 to proinflammatory M1 subtype contributes to a link to inflammation. This opens a new dimension for understanding obesity-induced inflammation.111, 112
Plankton and Plant Solutions
Relative to the management of lipogenesis and adipogenesis, ingredients from the oceans and forests keep offering new solutions. Although it is beyond the scope of this article to cover every new ingredient, a select few are discussed herein.
One naturally brominated diaryl ether from a sponge of Dysidea species has been isolated.113 In addition to its antibacterial properties,114 the compound induces adiponectin release from adipose tissue, enhancing the metabolism of type I muscle fibers and mitochondrial activity. This resulted in visible reductions in abdomen contour, as much as 2.8 cm in 28 days, and thighs, up to 2.1 cm in 56 days.115
Exopolysaccharides produced by one plankton target nocturnin in adipocytes via the modulation of circadian rhythms. Especially active during the night, these ingredients provide anti-cellulite, slimming and firming benefits.116
Hydroxycitric acid (HCA), obtained from fruit extracts of Garcinia spp, also shows clinical efficacy against adipose tissue via several biochemical mechanisms: inhibiting ATP citrate lyase and over-expressing leptin, TNF-α, resistin, PPARγ2, C/EBPα and SREBP1c genes in epididymal adipose tissue.30-33, 117 Garcinia lactone, a stable form of HCA, may provide the same benefits due to its in situ conversion into HCA. This aspect warrants further study.
Concluding Discussion: Disrupting the ‘Quick Fix’ Mentality
Over the years, consumers have been given the impression that given products would make their cellulite-free dreams come true just in time for swimsuit season. Brands have a tendency to introduce cellulite products close to warm weather months and market them with “quick-fix” claims. While the number of scientifically driven ingredients for body sculpting is growing, consumer skepticism persists over whether these products can deliver sustainable results.
If seasonal quick-fix marketing were to shift to year-round repair and prevention messaging, this could change not only consumer mentality, but also product preference. Examples of successful paradigm shifts exist in the marketing of sunscreen and anti-aging skin care in recent years, where a regimen of daily, year-round use has been emphasized. The best and most effective way to disrupt the marketing narrative regarding cellulite products is to educate the consumer about how preventing future adipose deposits is more important than spot-treating cellulite before heading pool-side.
By creating a multifunctional adipose and cellulite management product, brands will have a complete story to sell consumers on the necessity for daily, year-round use. And the new-era, “preventive strike against cellulite genesis” solutions envisioned here are the future wave for anti-cellulite and lipo-filling management product development.
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