cellulite and its treatment

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Review Article

Cellulite and its treatment

A. V. RawlingsAVR Consulting Ltd, Northwich, U.K.

Received 25 January 2006, Accepted 15 February 2006

Keywords: cellulite, conjugated linoleic acid, nuclear hormone receptors, papillae adiposae, ultrasound

SynopsisThe presence of cellulite is an aesthetically unac-ceptable cosmetic problem for most post-adolescentwomen. It is largely observed in the gluteal-fermoralregions with its ‘orange-peel’ or ‘cottage cheese’appearance. It is not specic to overweight womenalthough increased adipogenicity will exacerbatethe condition. It is a complex problem involvingthe microcirculatory system and lymphatics, theextracellular matrix and the presence of excess sub-cutaneous fat that bulges into the dermis. It hasbeen described as a normal condition that maximi-

zes subcutaneous fat retention to ensure adequatecaloric availability for pregnancy and lactation.Differences in the brous septae architecture thatcompartmentalize the adipose tissue have recentlybeen reported in women with cellulite comparedwith men. Weight loss has been reported toimprove the cellulite severity by surface topogra-phy measures although in obese subject’s skin dim-pling does not seem to change appreciably.However, histological analysis suggests that fatglobules retract out of the dermis with weightloss. Cellulite has been treated with massagewhich decreases tissue oedema but it is also likelyto have its effects at the cellular level by stimula-ting broblast (and keratinocyte) activity whiledecreasing adipocyte activity. In addition to mas-sage, effective topical creams with a variety of agents were used to ameliorate the condition.

Nevertheless, only a few studies are reported inthe scientic literature. Xanthines, botanicals, fra-grances and ligands for the retinoid and peroxisom-al proliferator-activated receptors appear to begiving some benet. Reducing adipogenesis andincreasing thermogenesis appear to be primaryroutes and also improving the microcirculationand collagen synthesis. Many agents are beinginvestigated for weight management in the supple-ment industry [hydroxycitrate, epigallocatechingallate, conjugated linoleic acid (CLA), etc.] andsome of these agents seem to be benecial for thetreatment of cellulite. In fact, CLA was proven

to ameliorate the signs of cellulite. One product,Cellasene, containing a variety of botanicals andpolyunsaturated fatty acids also appears to providesome relief from these symptoms. Although morework is needed, clearly these treatments doimprove the appearance of skin in subjects withcellulite. It is quite possible, however, that syner-gies between both oral and topical routes may bethe best intervention to ameliorate the signs andsymptoms of cellulite.

Re sume ´

La pre sence de cellulite est un proble `me cosme´tiqueesthe tique inacceptable pour la plupart des femmespost-adolescentes. On l’observe couramment dansla re gion glute ále femorale sous forme de ‘peaud’orange’. Il n’est pas spe ćique d’un surpoids chezla femme, bien qu’une augmentation d’adiposite ´ ex-acerbe le phe ńome`ne. C’est un proble `me complexemettant en jeu le syste `me micro circulatoire et lymp-hatique, la matrice extracellulaire et la pre ´sence

Correspondence: Anthony V. Rawlings, AVR ConsultingLtd, 26 Shavington Way, Kinsmead, Northwich,Cheshire CW9 8FH, U.K. Tel.: +44 160 6354535; e-mail:[email protected]

International Journal of Cosmetic Science , 2006, 28 , 175–190

ª 2006 Society of Cosmetic Scientist s and the Societe Francaise de Cosmetologie 175



d’un exce`s de graisse sous-cutane é dans le derme.Elle a e te decrite comme une condition normale quimaximise la retention sous-cutanee de graisse pourassurer une disponibilite ´ calorique ade ´quate lors dela grossesse et de la lactation. Des diffe ´rences dans

l’architecture breuse du ‘septae’ qui comparti-mente le tissus adipeux ont re ćemment e ´te rapport-ees apre s comparaison de la peau de femmessouffrant de cellulite et celle d’hommes. On aobserve´, apre s etude topographique de surface,qu’une perte de poids aggrave la cellulite, alors quechez des sujets obe `ses la surface de la peau ne sem-ble pas changer notablement. Cependant, une e ´tudehistologique sugge `re que les globules de graisses sere tractent lors d’une perte de poids. On traite la cel-lulite avec des massages qui diminuent l’œde `me destissus et qui ont e ´galement des effets au niveau cel-lulaire par stimulation des broblastes (et des ke ´ra-tinocytes) et diminution de l’activite ´ des adipocytes.En complement des massages, on applique de facontopique des cre `mes contenant diffe ´rents agents.Neanmoins, il existe peu d’e ´tudes scientiques surce sujet. Des xanthines, des de ´rive s botaniques, desparfums et des ligands des re ćepteurs du prolife ´ra-teur active ´ du re tinoide et du peroxysome semblentdonner de bons re ´sultats. La re ´duction de l’adi-poge ne se et l’augmentation de la dermoge ńe separaissent etre les premie `res causes de ces resultats,tout comme l’ame ´lioration de la micro circulationet la synthe `se du collage `ne. De nombreux agents

ont e te etudie s pour le contro ˆ le du poids dans l’in-dustrie des comple ´ments alimentaires (hydroxy-citrate galate d’e ´pichalocate ćhine, ECG, acidelinole ique conjugue ´ CLA, etc.) et quelques-uns deces agents semblent e ˆtre be ne ques au traitementde la cellulite. En fait, on a montre ´ que le CLA con-duisait a` quelques ame ´liorations des manifestationsde la cellulite. Un produit - le CELLASENE - conten-ant divers de ´rive s botaniques et des acides gras polyinsature ´s apparait e ´galement efcace vis-a ` -vis deces symptoˆ mes. Bien que davantage de travail soitnecessaire, il es clair que ces traitements ameliorentl’aspect de la peau chez des sujets souffrant de cellu-lite. Il est tout a ` fait possible, cependant, que dessynergies entre la voie orale et la voie topique puis-sent e tre la meilleure facon d’ame ´liorer les signes etles symptoˆ mes de la cellulite.

Introduction

Cellulite is a cosmetically unacceptable problemthat most women experience at some point in

their lifetime. It occurs mainly on the lower limbs,pelvic region (gluteal-fermoral regions) and abdo-men and is characterized by an ‘orange peel’ or‘cottage cheese’ appearance [1]. Approximately85% of women over the age of 20 have some

degree of cellulite [2, 3]. It has been described byGoldman [4] as a normal physiological state inpost-adolescent women which maximizes adiposeretention to ensure adequate caloric availabilityfor pregnancy and lactation. This disorder shouldnot be confused with obesity where only adipo-cytes hypertrophy and hyperplasia occurs.Although this also occurs in subjects with cellulite,there are also several structural alterations in thedermis and microcirculatory alterations exist.Increased interstitial uid protein concentrationsand interstial pressure have been reported and areduced blood ux into the tissue culminating indecreased skin temperature on affected sites. Typ-ical manifestations of the problem can be seen inFigs 1 and 2. Figure 1 shows the cellulite gradeused by Rossi and Vergnanini [5] at rest and aftergluteal contraction, whereas Fig. 2 shows the pho-tonumerical scale used by Perin et al. [6] after astandardized compression of the thigh area.

The anatomy of cellulite can be clearly seenfrom the studies of Pierard et al. [7]. The super-cial fat lobules (papillae adiposae) that protrudeinto the dermis can be clearly seen in Fig. 3a inautopsy section of the skin (see Fig. 3b for sche-

matic fat projections into the dermis). Recently,magnetic resonance imaging and spectroscopyhave been applied in vivo to understand the condi-tion better. First, Querleux et al. [8] at L’OrealRecherche quantied deep indentations of adiposetissue into the dermis and a great increase in thethickness of the inner fat layer in women with cel-lulite. As can be seen in Fig. 4 deep adipose inden-tations are clearly visualized and the Camper’sfascia can been seen to separate the adipose tissuein two layers. The dermal thickness was similarbetween women with and without cellulite but thesubcutaneous adipose thickness layer was vetimes thicker in women with cellulite (24.81 mmvs. 4.31 mm as can be seen in Fig. 5). Equallyimportantly, they described a higher percentage of brous septae perpendicular to the skin surface(Figs 6 and 7). Mirrashed et al. [9] and colleaguesat Procter and Gamble made similar observationson the extrusion of underlying adipose tissue intothe dermis and found that the percentage of adi-pose tissue vs. connective tissue in a given volume

ª 2006 International Journal of Cosmetic Science , 28 , 175–190176

Cellulite and its treatment A. V. Rawlings



of hypodermis and that the percentage of hypoder-mic invaginations correlate with cellulite grade(Fig. 8). Most recently, in pilot studies, Callaghan[10] used in vivo confocal microscopy to evaluatethe condition. Compared with male skin, striaewere seen penetrating within the epidermis. Thecollagen had a dense appearance and stretched inone direction and the epidermis was thin. Clearlycellulite is a condition of altered connective tissuematrix as well as increased adipogenicity.

A variety of treatments have been proposed forthe treatment of cellulite with weight loss beingthe most frequently employed. Skin massage treat-

ments are used and a variety of topical agents aswell as oral supplements.

Targets for cellulite treatment

Rossi and Vergnanini [5] reviewed various targetsthat need to be corrected in cellulite and will bedescribed below. In their analysis, broblasts, acti-vated by oestrogen, increase Glycosaminoglycan(GAG) synthesis which then leads to increasedinterstitial osmotic pressure and uid retention.This consequently compresses blood vessels provo-king tissue hypoxia. Local inammatory cytokines

Figure 1 Cellulite grade at grade II(i), grade III (ii) and grade 4 (iii) atrest (a) and after gluteal contraction(b). From Rossi and Vergnanini [5].

Figure 2 Photonumerical scale representative of the different grades of cellulite on compressed thighs: from no cellulite(left) to very severe signs of cellulite (right). From Perin et al. [6].

ª 2006 International Journal of Cosmetic Science , 28 , 175–190 177




also induce collagen synthesis. Increased capillarypressure, a decrease in plasma osmotic pressureand an increase in interstitial osmotic pressure (or

a decrease in lymphatic ux) lead to intercellularoedema. The increased osmotic forces will alsoinuence the cellular phenotype of the broblasts.

(a)

(b) Figure 3 (a) Autopsy of ampu-tated leg. Complex network of hypodermal brous strands incellulite. Their thickness isuneven. There is no real septumpartitioning the fat lobules. FromPierard et al. [7]. (b) A sche-matic diagram of skin structureshowing ve zones. The greylayer is the surface of the skin:the epidermis. Zone 1 is thedermis. Zone 2 is the extrusionof the hypodermis into thedermis. Zones 3–5 are the upper,middle and lower parts of the

hypodermis. From Mirrashedet al. [9].

Figure 4 Magnetic resonance images of adipose tissue. (a) Hypodermis of the whole thigh. Hypodermis appears hyper-intense. The dermis is not visible at this spatial resolution; (b) high spatial resolution 2D image, 3 mm thick, of hypo-dermis on the dorsal side of the thigh of a woman with cellulite. With a resolution of 70 l m in the depth of the skin,Camper’s fascia separates the adipose tissue in two layers. Deep adipose indentations into the dermis are clearly visual-ized. Fibrous septae appear as hypointense thin structures. (c) Two contiguous thin images from a series of 64 images.A slice thickness of 0.5 mm offers an optimal contrast between fat lobules and brous septae allowing the 3D recon-struction of the brous network architecture. From Querleux et al. [8].





Equally, as discussed by Pierard in this series of articles, however, the progressive vertically orien-ted stretch in the subcutis from the hypertrophicadipocytes also occurs in cellulite and the bro-blasts will accommodate to this by remodelling theextracellular matrix.

The anatomy of the subcutaneous fat includestwo layers separated by a supercial fascia. Thelayer closest to the dermis is called the areolarlayer and is formed by globular large adipocytesarranged vertically. The blood vessels in this region

are numerous and fragile. In the deeper lamellarlayer the cells are smaller and arranged horizon-tally whereas the blood vessels are larger. When aperson gains weight it is this layer that enlarges.Women (and children) have a thicker areloar layer.This layer is predominantly under the control of oestrogen and in the femoral region the adipocytesare more resistant to lipolysis. Several hormonesstimulate lipogenesis (insulin, oestrogen, prolactin)but it is decreased by others; catecholamines stimu-late lipolysis through the activation of adenylcyclase. However, contrary to popular belief, it isinsufcient to just induce adipocytes lipolysis toremove the excess triglycerides in these cells. Thereleased fat would just be transferred into the cir-culatory system and processed by the liver whichthen increase the levels of very low-density lipopro-teins in the blood which on return to the subcuta-

Women with cellulite

Women with no celluliteMen

90

80

70

60

50

40

30

20 % O

f f i b r o u s s e p t a e

10

0Directions perpendicular

to the skin +/– 15°Directions tilted at 45°

to the skin +/– 30°Directions parallelto the skin +/– 15°

Figure 7 Structural patterns of thebrous septae network according tosex and presence of cellulite. Thesequantitative ndings give moreevidence about the heterogeneity of the septae, and suggest modellingthe 3D architecture of brous septaeas a perpendicular pattern inwomen, whereas it is tilted at 45 °

in men. From Querleux et al. [8].

Figure 6 Visualization of the 3D architecture of brous septae in subcutaneous adipose tissue. (a) Woman with cellu-lite; (b) woman without cellulite; (c) man. From: Querleux et al. [8].

Women with celluliteWomen with no celluliteMen

40

35

25

15

30

20

10

5

00 2 4 6

Outer layer (mm)

I n n e r l a y e r ( m m

)

8 10 12

Figure 5 New characteristic marker of cellulite. Mag-netic resonance imaging shows that women with cellu-lite have a much greater increase in the thickness of thedeep inner adipose layer compared with normal womenor men. From Querleux et al. [8].





neous fat layer will be utilized again and after theaction of lipoprotein lipase to make more adipo-cyte triglyceride. Although this is an energeticallyexpensive and inefcient way of redirecting trigly-ceride transport around the body some calories arelost in this futile cycle. However, the most efcient

route to adipocyte fat removal would be to increasethe levels of mitochondrial uncoupling proteinsand ‘burn’ the fat locally (thermogenesis). Severalagents are reported to enhance this process.

As many of the nuclear hormone receptor lig-ands [e.g. the retinoid receptors and the peroxi-somal proliferator-activated receptor (PPAR)]inuence the skin cells involved in forming andaggravating the cellulitic condition it is appropri-ate to give a summary of their general mechanismof action and some of their effects in other condi-tions than cellulite.

Gene expression is regulated through the inter-play of specic DNA-binding transcription factors.On binding ligands co-repressors dissociate fromthe transcriptional machinery complex and coacti-vators bind to initiate gene transcription. Nuclearhormone receptors are transcription factors thatregulate many cellular functions. This superfamilyof receptors has been segregated into four majorsubgroups. The class II subfamily consists of nuc-lear receptors that form heterodimers with the reti-

noid X receptor (RXR) [11] which for exampleinclude the retinoic acid receptor (RAR) and thePPAR [12]. Stimulation of these receptors, in par-ticular, regulates keratinocyte proliferation and dif-ferentiation, inuences melanogenesis andstimulates dermal matrix reconstruction.

Retinoid receptors

Vitamin A is a recognized and well-establishedanti-ageing active. Originally used as an anti-acnetreatment, retinoic acid is now used to treat thesigns of ageing. Retinoic acid mediates its effectvia binding to its nuclear transcription factors.The RAR binds all trans-retinoic acid (RA) and itsstereoisomer 9-cis RA; and the RXR binds 9-cisRA. A common feature of these receptors is thatthey bind to certain regions of DNA known as hor-mone response elements and thereby initiating lig-and-dependent gene transcription. The retinoidtranscription factors bind to a retinoic acidresponse element in the promoter of genes com-posed of a 6-bp sequence (AGGTCA) (Fig. 9). Sim-ilar base pair sequences are shared by othermembers of this superfamily which differ only bythe insertion of additional base pairs. RARs andRXRs are known to contain at least three differentsubtypes: alpha, beta and gamma each of which

Figure 8 Skin of two females bothfrom low body mass index group:(a) cellulite grade ¼ 2.5, hypodermis16.2 mm; (b) cellulite grade ¼ 0,hypodermis 11.3 mm. From Mirra-shed et al. [9].





have several isoforms. The RXRs predominate inhuman skin especially RXRalpha. Of the RARs87% are RARgamma and 13% RARalpha. Onlysmall amounts of RARbeta are found in dermalcells and melanocyes. Retinoic acid treatmentresults in major epidermal changes only weeksafter treatment but in the longer term dermaleffects are observed (angiogenesis, synthesis of new connective tissue components and increasesin the numbers of more active broblasts). Varaniet al. [13] has also reported that 0.5% retinol(ROH) is as effective as 0.05% RA. However, thislevel of ROH cannot be used in cosmetic productsand even if it was allowed the irritation levels arecomparable between the two agents. Nevertheless,

topical application of retinol can reverse the skinchanges associated with ageing by increasingbroblast proliferation, increasing skin collagenlevels and decreasing Matrix metalloprotease(MMP) levels [13].

Peroxisome proliferator-activated receptors

Peroxisome proliferator-activated receptors (PPAR)are a recently discovered family of nuclear tran-scription factors [14, 15] and three PPAR receptortypes, PPARalpha, PPARbeta or delta, PPARgam-ma have been characterized. PPARs bind to theperoxisome proliferator response element withinthe promoter region of the DNA in the target genein the form of heterodimers with the RXR (Fig. 9).

Peroxisome proliferator-activated receptors areactivated by the brate hypolipidaemic drugs, fattyacids, eicosanoids and prostanoids but of thesechemical types the fatty acids are of the mostinterest for skin applications. The ability of satur-ated, monounsaturated and polyunsaturated long

chain fatty acids to bind and activate all threePPAR subtypes has been well documented. How-ever, saturated fatty acids have very low activityas PPAR ligands, whilst monounsaturated fattyacids are substantially more active and polyunsat-urated fatty acids are generally the most potentwith the optimum chain length required for acti-vation being between C18 and C22. In terms of receptor subtype selectivity, the saturated andpolyunsaturated fatty acids do not differentiatebetween PPARs, whereas, in contrast, the mono-unsaturated fatty acids appear to have a highafnity for PPARalpha. Gamma-linoleic acid,myristic and palmitic acids also show a greaterafnity for PPARalpha and PPARdelta compared

with PPARgamma but their IC 50 values are stillin the micromolar range [16].

Peroxisome proliferator-activated receptors wererst identied in the epidermis in 1992. However,it was not until recently that the importance of PPARs in epidermal homeostasis has becomeapparent with the discovery that activation of PPARalpha, with either lipids or the hypolipidae-mic drug clobrate, can accelerate epidermalbarrier formation and induce epidermal differenti-ation. Rivier et al. [17] at Galderma rst reportedthat PPARalpha ligands inuence lipid biosyn-thesis in living skin equivalents. Keratinocyteserine palmitoyl transferase and glucocerebrosidaseactivities were increased in these studies and therewas a particular increase in ceramide biosynthesisparticularly for ceramides 1, 2 and 3 (CER EOS,CER NS and CER NP).

Peroxisome proliferator-activated receptor deltawas recently observed to be the predominantPPAR subtype in human keratinocytes, whereasPPARalpha and gamma were only induced during

DNA RAR or PPAR responsive element

9 cis RA

RXR PPAR

Ligand PPAR

Transcription

Coactivator/Co-repressor

Figure 9 Mechanism of bindingand action of ligands to the retinoidand peroxisomal proliferator-activa-ted receptors. From Wiechers et al.[23].





epidermal differentiation suggesting different recep-tors are used during differentiation [18]. PPARdeltaligands were found to be the most potent in indu-cing epidermal differentiation (tetrathioacetic acid)by increasing involucrin and transglutaminase

while decreasing proliferation. This is consistentwith PPARdelta-decient mice exhibiting anexacerbated epidermal hyperplastic response toTPO in contrast to the minor abnormalities seenin PPARalpha-decient mice.

Studies from scientists within my previousresearch group at Unilever has highlighted thebenets particularly of petroselinic acid [19]and conjugated linoleic acid (CLA; Unileverpatents: US6423325, US6403064, US6287553,US6042841, WO0108650, WO0108652,WO0108649) as potent PPARalpha activatorsimproving epidermal differentiation, reducinginammation, increasing extracellular matrix com-ponents and eliciting skin lightening. In vitro ,increases in levels of transglutaminase, involucrin,laggrin and corneocyte envelope formation wereobserved in keratinocytes whereas increased levelsof pro-collagen 1 and decorin were observed forbroblasts. These effects were conrmed in vivoby short-term patch testing studies over a 3-weekperiod and increases in the levels of involucrin andlaggrin were also observed. These biochemicalchanges translated into improvements in the signsof photodamage and skin tone in a 12-week clinical

study on forearm skin [20]. There is further evi-dence that PPAR ligands can also mitigate the pig-mentation process and induce skin lightening [21,22]. Wiechers et al. [23] reported that octadenedioicacid is a pan PPAR agonist and reduces tyrosinasetranscription. All PPARs are found in adipocytes.

Some of the approaches taken to reduce theappearance of cellulite will be reviewed and wherepossible with examples of the effect of agents fromboth a topical and oral perspective.

Treatment of cellulite

Massage

Vigorous massage is used to encourage removal of interstitial uid and improve lymphatic drainagein individuals with decreased venous return. Ini-tially the skin improvements are short term and just related to the removal of excess uid [1].However, more prolonged treatments may improvethe underlying condition. LPG Endermologie (LPG

Endermologie USA, Fort Lauderdale, FL, USA) is amachine-assisted massage system that allows pos-itive pressure rolling in conjunction with appliednegative pressure to the skin which improves bodycontour and skin texture. Chang et al. [24] repor-

ted up to 1.83 cm reduction in body circumfer-ence when using this equipment. However, Collinset al. [25] reported that 28.5% of subjects usingthis approach over a 12-week period noticedimprovements in their cellulite condition. Obvi-ously, use of topical creams involves a massagingaction and the direct physical stimulus of rubbinga cream which may contribute to an improvementin the condition with time. The effects may not befantasy as research on the mechanobiology of skinhas increased [26]. Although Yucatan minipigs donot suffer from cellulite Adcock et al. [27] showedthat deep mechanical massage enhances the pres-ence of longitudinal collagen bands whereas dis-tortion and disruption of adipocytes was noted.Fibroblasts are known to respond to tensional for-ces in the extracellular matrix and produce colla-gen. Increases in keratinocyte proliferation alsooccur when stretched possibly leading to a thickerepidermis. Conversely, mechanical stretching of adipocytes inhibits their differentiation and is rela-ted to a reduction in PPARgamma levels via acti-vation of extracellular signal-regulated proteinkinase pathway [28]. Collectively, these ndingsprovide a molecular basis for the physiological sig-

nicance of the local application of mechanicalstimuli, massage in this case, to the skin and thepossible relief from the signs of cellulite.

Topical treatments

As with many skin conditions, cellulite is a complexcondition and as a result combinations of differentingredients to inuence the different aspects of thepathophysiology of the condition is recommended.It goes without saying that the concentration of theingredient has to reach the site of action and at theright concentration for its effects to be realized ashas been outlined by Wiechers et al. [29]. Equally,however, cellulite is a condition that develops overyears and will take several months before any effectmay come apparent to the clinician and well as thesubject. However, in most cases the individual ismore likely to perceive an improvement in the con-dition before changes in the clinical grade occurs.Using the photonumerical scale outlined in Fig. 2,Perin et al. [6] showed the improvement in cellulite





with a commercial cream from Christian Dior com-pared with its placebo. The variation and improve-ment in treatment effect can see in Fig. 10 andaverage scores decreased from 3.64 to 2.81(P < 0.05). A signicant decline in the thickness of the thigh subcutaneous adipose tissue was alsodetermined by ultrasound imaging (Fig. 11) andthe self-perception data are given in Table I.

XanthinesMethylxanthines are common ingredients used incellulite products, e.g. caffeine, aminophylline, the-

ophylline, etc. and are used because of their pro-posed effect on adipocyte lipolysis via inhibition of phosphodiesterase, and increasing cyclic adenosinemonophosphate (AMP) levels. Nevertheless, on itsown aminophylline was reported not to improve thecondition over a 12-week period. Equally, Collinset al. [25] also reported that only 10% of the subjects observed an improvement in their condition.

Greenway and Bray [30] demonstrated a signi-

cant reduction in thigh thickness when aminoph-ylline was used together with isoproterenol (abeta-adrenergic receptor agonist and yohimbine,an alpha-agonist). However, in these studies thephosphodiesterase inhibitor was also reported tobe effective on its own.

Uncoupling proteins (UCP) are present in themitochondria of all cells and they have the capabil-ity of dissipating the mitochondrial proton gradientgenerated by the respiratory chain. It is throughthis process that we keep warm in the cold, i.e. non-shivering thermogenesis. UCP-1 is expressed inbrown adipose tissue of which humans have littlewhile UCP-2 is expressed in white adipose tissue. Intransgenic animals that over express these proteinshave a reduced adipose tissue mass and, thus, theirexpression in humans adipose tissue may help withthe expression of cellulite. More work is needed inthis area but caffeine increases UCP-3 levels in sub-cutaneous white adipose tissue adipocytes and wassynergistic in the presence of noradrenaline [31].Ligands for the retinoid and PPAR receptors are also

Improvement

Scores obtained after the 2-month treatment–3 –2 –1 0 1 2 3

S u b j e c t s

Aggravation

Figure 10 Variation of celluliteindex after 2 months of treatment.A signicant effect of the slimmingproduct was observed with improve-

ment of the cellulite index in 21subjects. From Perin et al. [6].

T + 1 month

42

0–2

–4–6–8

–10

–12–14

% O f

v a r i a t i o n o f t h

i c k n e s s r e l a t i v e

t o T

0 T + 2 month ActivePlacebo

Difference

Figure 11 Variation of the thickness of thigh subcuta-neous adipose tissue determined by ultrasound imagingafter 2 months treatment with either the active slimmingpreparation or placebo. A ) 11.4% signicant differentialslimming effect was observed (active-placebo;P < 0.0001). From Perin et al. [6].





capable of inducing these effects (see later in oralsupplement section).

Herbal treatmentsMany herbal extracts are used in slimming prod-ucts such as verbena, green tea, lemon, kola nut,

fennel, algae, ivy, barley, strawberry, marjoramand sweet clover [32]. Some are reported toimprove the peripheral microcirculation and facili-tate lymphatic drainage. One of the few studiesthat have been reported scientically is that of Buscaglia and Conte [33] who examined the effectof caffeine, horsechestnut, ivy, algae, bladder-wrack, plankton, butcherbroom and soy proteinapplied for 30 days. A 2.8 mm decrease in subcu-taneous fat thickness was reported which reap-peared in the regression phase of the study. Raoet al. [34] evaluated a cream containing black pep-per, sweet orange peel, ginger root extract, cinna-mon bark extract, capsaicin, green tea and

caffeine which was applied under occlusion withneoprene shorts. Of the 34 subjects who completedthe study, 63% (21/34) noticed an improvementin their cellulite and 62% (13/21) reported agreater effect for the treatment. Dermatologistsfound the thighs that were treated with the active

product showed a greater improvement than theplacebo (Fig. 12). Thigh circumference reductionwas 1.9 cm for the active product and 1.3 cm forthe placebo. The results of Perin et al. in Figs 10and 11 were obtained from using a hydroglycolicgel containing extracts of Terminalia seracea , Visnagavera , Plectreinthus barbatus and Cola lipa togetherwith cyclic AMP (courtesy of F. Bonte).

FragrancesInhalation of essential oils such as pepper, estra-gon, fennel or grapefruit oils increase sympatheticneural activity by up to 2.5-fold. Activation of thesympathetic nervous system this way in combina-

Table I Main results of self-percep-tion in cellulite study

CelluliteSmoothingof the skin Firming Silhouette

Active Placebo Active Placebo Active Placebo Active Placebo

Effect (%) 86.7 43.3 90.0 60.0 56.7 53.3 80.0 40.0No effect (%) 13.3 56.7 10.0 40.0 43.3 46.7 20.0 60.0Signicance <0.001 NS <0.0001 NS NS NS <0.01 NS

From Perin et al. [6].

sk eew4retfAerofeB(b)

strohsenerpoeN

(a)

(c)Figure 12 (a) The modied bioce-ramic-coated neoprene shorts withone leg removed, to provide occlu-sion on one thigh only. (b, c) Photo-graphs taken immediately beforeand after 4 weeks of Spa MD Anti-Cellulite Cream TM with occlusion bya Bioceramic-Coated Neoprene Gar-ment for two subjects. Courtesy of La Jolla Spa MD and from Rao et al.[34].





tion with a topical caffeine-containing cream hasbeen reported to have a slimming effect. Hariyaet al. [31] proposed the UCP theory in which inha-lation of an appropriate odorant stimulates thesecretion of noradrenaline which acts in synergy

with percutaneously absorbed caffeine to bothsimulate lipogenesis and thermogenesis to ‘burn’the locally produced fat (Fig. 13). Although cellu-lite was not graded in these studies, the averageweight loss was 1.1 kg and 25% of subjects lost2 kg with decreases of 1.5 and 1.3 cm at thewaist and hips.

RetinoidsKligman et al. [35] used retinol (0.3%) over a6-month period and demonstrated an improve-ment in cellulite; 12 of 19 subjects showed animprovement in the condition. These effects maybe due to the known effects of retinoids increasingthe dermal content and architecture of collagenand dermoepidermal proteins together withanchoring and elastic brils. However, Pierard-Franchimont et al. [36] could not nd any changein the orange peel condition but did observe anincrease in skin elasticity and a decrease in its vis-cosity. Increased factor XIIIa+ dendrocytes wereobserved indicating an improvement in skin condi-tion. Later Bertin et al. [37] tested the effects of retinol combined with caffeine and ruscogeninedecreased the orange peel effect and improved

cutaneous microcirculation. However Garcia et al.[38] and Machinal-Quelin et al. [39] proposed thatretinol itself is also anti-adipogenic by inhibitingthe differentiation of human adipocyte precursor

cells by reducing the expression of the ob gene.Nevertheless, on its likely conversion to retinoicacid in vivo, it is also capable of increasing mitoch-ondrial coupling proteins, thereby contributing tothe reduced subcutaneous fat levels through cellu-lar heat dissipation [40].

PPAR agonistsAgonists of PPAR are known to improve epidermaldifferentiation, increase collagen levels, suppresssebogenesis, are anti-inammatory and skin-ligh-tening agents [12]. They also increase UCP levels.Thus, like retinoids they deliver pleotropic benets.The use, however, requires a pan-agonist activityas stimulation of PPARgamma alone increases ad-ipogenicity. It is therefore not too surprising that

these have been evaluated as anti-adipogenic com-pounds and as anti-cellulite treatments. CLA hasbeen shown at Pentapharm to prevent lipid accu-mulation in adipocytes in vitro (Fig. 14) and in

×

Noradrenaline(catecholamines)

Sympathetic nerveactivating odorantsCaffeine

Neutral fat Free fatty acid

Conventional approach New approach

Hydrolysis Burning

New theory(UCP theory)

Apply Smell

Thermalenergy

UCP

Figure 13 Novel slimming theory(uncoupling proteins theory, UCP).Activation of the sympatheticnervous system by inhalation of anappropriate odorant prompts secre-tion of noradrenaline. The increaseof noradrenaline acts synergisticallywith percutaneously absorbed caf-feine to promote gene expression of the UCP, that burns up free fattyacids in adipose tissue. From Hatiyaet al. [31].

Number of lipid droplets

0

200400

600

800

1000

1200

1400

Control – 0 .0 30000 .0 3000 .0 300

D r o p

l e t s ×

1 0 3 c m

– 2

LC% A

*

*

*

Figure 14 Histogram showing reduced triglyceride accu-mulation in adipocytes following conjugated linoleic acidtreatment. Courtesy of D. Imfeld, Pentapharm.





in vivo studies CLA reduced adipose invaginationinto the dermis as judged by ultrasound andimproved the appearance of cellulite (Fig. 15)(D. Imfeld, personal communiation, Pentapharm).

AlphahydroxyacidsAlphahydroxyacids (AHAs) and particularly lacticacid have been proposed in the treatment of cellu-lite [41]. However, there are no reported studies.Nevertheless, as these agents have an anti-ageingeffect (increased collagen levels) and improve thesigns of photodamaged skin [42] as well asimproving epidermal differentiation and barrierfunction as reported by Rawlings et al. [43] andBerardesca et al. [44] it is likely that this class of ingredients will improve the skin surface orangepeel appearance in cellulite.

Oral treatments

Many of the above-mentioned agents are also usedin oral supplements for the treatment of celluliteand like the topical treatments there are very fewscientically reported studies examining theireffects on improving the condition. As a result,examples will be given from the recent literature onagents that also help with weight control as thesemay also inuence the appearance of cellulite.

PPAR agonists

Oral supplementation of PPAR agonists has alsobeen considered by the supplement industry. Infact, an oral intervention study on mice for4 weeks CLA and docosahexanenoic acid com-pared with linoleic acid decreased subcutaneousfat thickness which was related to reduced size of

adipocytes. Increased collagen levels were alsoobserved [45]. In humans Birnbaum [46] com-pared the effects of an undisclosed herbal anti-cel-lulite pill with increasing concentrations of CLAover 60 days [group 1, herbal pill (HP) alone;

group 2, HP plus 400 mg CLA; group 3, HP plus800 mg CLA and each group consisted of 20women]. These treatments had a benecial effectin 75% of the women who took the pills and thethigh circumference was reduced by an average of 0.88 inch. Figure 16 shows the improvements inthigh cellulite appearance and thigh circumferencemeasurements on completion of the study.Improvements in the microcirculatory patternswere also observed. Although no more studieshave been conducted on cellulite, CLA has repeat-edly been shown to reduce body fat mass in obeseindividuals with a corresponding increase in leanbody mass, i.e. muscle [47].

Centella asiaticaHachem and Borgoin [48] reported on the effectsof Asiatic centella extract given orally one a day(60 mg) for 90 days. In these studies there was asignicant reduction in the diameter of adipocytesespecially in the gluteo-femoral region and adecrease in interadipocyte brosis. In addition toantioxidants such as quercetin, these extracts willcontain ursolic acid lactone, ursolic acid, pomolicacid, 2-alpha,3-alpha-dihydroxyurs-12-en-28-oic

acid, 3-epimaslinic acid, asiatic acid, corosolic acidand rosmarinic acid. The ursane- and oleanane-type triterpene oligoglycosides such as centellas-aponins B, C and D are also present and althoughmechanisms were not discussed at the time it ishighly likely that these agents are PPAR agonists.

tnemtaerterofeB

0yaD

tnemtaertretfA

48yaD

Figure 15 Decrease in cellulitegrade following 84 months topicaltreatment with conjugated linoleicacid. Courtesy of D. Imfeld, Pentap-harm.





HydroxycitrateHydroxycitrate from Garcinia cambogia , also knownas Malabar tamarind , is a lipogenesis inhibitor and ithas been used on its own or together with niacin-bound chromium or Gymnema sylvestre (gymnemicacid) to help with weight control and reduce bodyweight [49]. It is highly likely that these willimprove the appearance of cellulite. Of note this is ahydroxyacid and may improve collagen synthesis just like other AHAs. Exploitation of these types of agents has exploded in the beverage markets.

Green tea and polyphenolsAlthough not tested for their effects on cellulite,green tea extracts have become a topic of interestfor the treatment of obesity. Chantre and Lairon[50] have shown that after 3 months of interven-tion an 80% ethanolic dry extract standardized at25% catechins decreased body weight by 4.6% and

waist circumference by 4.48%. This was proposedto be acting by inhibiting gastric lipases and increas-ing thermogenesis. More recently Wolfram et al.[51] and Klaus et al. [52] reported that epigallocate-chin gallate (EGCG) prevented obesity in rodents.

Fatty acid synthase and acetyl-CoA carboxylasemRNA levels were reduced and EGCG inhibitedadipocytes differentiation in vitro . It is interesting inthis respect that green tea leaf extracts increasedPPARalpha and gamma protein expression [53].Black tea extracts also appear to have moderatePPAR activity, albeit lower, than green tea extracts.

CellaseneCellasene is a herbal supplement sold for improvingthe appearance of cellulite by Medestea (Torino,Italy). It contains Ginko biloba, sweet clover, seaweed, grape seed oil and evening primrose oil. Lis-Balchin [54] failed to observe any improvement inthe cellulite condition over 2 months but no bioin-strumental methods were used in this study. How-ever, Leibaschoff et al. [55] testing a slighty differentformula with sh oil and borage oil in place of theevening primrose oil (two capsules per day) foundimprovements in the lipoedema and skin muscularfascia diameter. About 71% of subjects had somesymptom improvements. Obviously, this product iseffective through a variety of mechanisms but especi-ally on adipocyte lipolysis, cutaneous microcircula-tion and collagen synthesis. However, as the authors

explain the grape seed extract is a powerful antioxid-ant and will act on the microvascular system, Ginkobiloba also effects the vascular system, Asiatic centellatriterpenoids favour lymphatic drainage and stimu-lates synthesis of the extracellular matrix, Mellilotusofcinalis also improves capillary resistance whereasFucus vesiculosus inuences the metabolic activity insubcutaneous fat and in fact 30% of subjects receiv-ing the Cellasene-containing focus extract experi-enced an improvement in their body contourproles. Further testing on a newer formulation isongoing which contains Vitis vinifera , Ginko biloba,Centella asiatica , Melilotus ofcinalis , Fucus vesiculosus ,shoilandborageoil (see Distante et al., Int. J. Cosmet.Sci. 28 , 191–206 (2006)).

Conclusions

Cellulite is a cosmetic problem and is of increasingconcern for women with its ‘orange-peel’ or ‘cottagecheese’ appearance affecting at least 85% of women. It is not specic for overweight women

1.0(a)

(b)

0.8

0.6

0.4 L o s s

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I m p r o v e m e n t

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75.0

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0.88

0.0

80

70

60

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20

10

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Group 1 Group 2 Group 3

Group 1 Group 2 Group 3

Figure 16 (a) Standardized thigh circumference meas-urements at and of oral conjugated linoleic acid (CLA)treatment. Group 1: Herbal anti-cellulite pill. Group 2:Herbal pill plus 400 mg CLA. Group 3: Herbal pill plus800 mg CLA. (b) Percentage of women showingimprovement in thigh cellulite at end of study. Group 1:Herbal anti-cellulite pill. Group 2: Herbal pill plus

400 mg CLA. Group 3: Herbal pill plus 800 mg CLA.From Birnbaum et al. [46].





although increased adipogenicity will exacerbatethe condition. It is a complex problem involving themicrocirculatory system and lymphatics, the extra-cellular matrix and the presence of excess subcuta-neous fat that bulges into the dermis. Differences in

the septae architecture have recently been reported.Weight loss has been reported to improve thecellulite severity by surface topography measuresalthough on obese subject’s skin dimpling does notseem to change appreciably [56]. However, histo-logical examination suggests that fat globulesretract out of the dermis with weight loss.

Cellulite has been treated by massage and top-ical or oral treatments. Massage will reduceoedema but there is also some evidence forincreased collagen synthesis after such treatmentsalbeit in animal studies. Equally, its benets couldbe via its likely effects on stimulating broblast(and keratinocyte) activity while decreasing adipo-cytes activity. Nevertheless a variety of agents areusually used in these topical creams but with fewstudies reported. Xanthines, botanicals, fragrancesand ligands for the retinoid and PPAR receptorsappear to be giving some benet. Reducing adipo-genesis and increasing thermogenesis appears tobe primary routes while also improving the micro-circulation and collagen synthesis.

Orally, many agents are being investigated forweight management (hydroxycitrate, EGCG, CLA,etc.) and some of these agents seem to be benecial

for the treatment of cellulite. In fact, CLA wasshown to ameliorate the signs of cellulite. One prod-uct, Cellasene from Medestea, containing a varietyof botanicals and polyunsaturated fatty acids alsoappears to provide some relief from these symptoms.

Regular exercise and an appropriate diet can helpcontrol weight and thereby the appearance of cellu-lite. Like the supplement industry, the food industryhas extensive research programmes investigatingthe effects of CLA, diglycerides, medium chain tri-glycerides, green tea, caffeine, capsaicin and cal-cium on weight control. These approaches may alsobe useful for the treatment of cellulite. It is quitepossible, however, that synergies between both oraland topical routes may be the best intervention toameliorate the signs and symptoms of cellulite.

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