The asymmetric distribution of fat in the human body has been a beauty and health concern since ancient times. Visual esthetics of body fat—either too little or too much of it—can cause social inequity. Adipose tissue, adipocytes, adiponectin, body fat and triglycerides are among a flotilla of adiposity-related terminology popular in the vocabulary of body weight and physical-appearance-conscious consumers.

The adage that body fat is controlled by a fat gene and almost nothing can be done to override its action can be disheartening to consumers who are dedicated to managing their body weight, shape, appearance and esthetics—yet experience slow progress or even reversal of achieved weight loss in due time.

An Introduction to Adiposity
Adipocytes are a major constituent of adipose tissue that controls energy balance by storing triglycerides in periods of energy excess and mobilizing it during energy deprivation.

Adipocytes also secrete numerous lipid and protein factors and are considered to constitute a major endocrine organ.
Adipogenesis is the process during which fibroblast-like pre-adipocytes develop into mature adipocytes.

White adipose tissue (WAT) and brown adipose tissue (BAT) are the two most well known types of adipose tissue, along with a few functionally distinct variants such as beige and pink. Different adipose tissues have varying functions.¹ WAT are unilocular cells that store body fat wherein a large lipid droplet is surrounded by a layer of cytoplasm. BAT are multilocular cells that have lipid droplets scattered throughout cytoplasm. The brown color comes from the large quantity of mitochondria present in the cell, which makes them thermogenic cells that protect animals against obesity and metabolic disease. Adipocytes are never lost, even after weight loss. The adipocytes merely gain or lose fat content to adjust for body weight changes. If the adipocytes reach their maximum capacity of fat, they may replicate to allow additional fat storage.

Harnessing Adipocytes
Adipocytes are formed by the differentiation of pre-adipocytes, which are undifferentiated fibroblasts. Signal molecules, the identity and biochemical mechanism of which have been unknown, control the differentiation of stem cells into WAT or BAT. Recently, retinoblastoma-like protein 1 (p107) has been found to be a key regulator for adipocyte lineage-fate of stem cells.² p107 is strictly expressed in the stem cell compartment of white adipose tissue and completely absent in brown adipose tissue. p107, in a nut-shell, directs cells to have preference for white adipose tissue.

The up- or down-regulation of p107 can lead to the management of “good (BAT)” or “bad (WAT)” adipose tissue in the human body. Alternatively, the conversion of WAT into BAT could be a strategy to increase energy expenditure at the expense of energy storage. The zinc finger transcription factor Prdm16 controls the thermogenesis in both brown and white adipose tissues.

BAT mass and its metabolic activity could be up-regulated by several transcription factors, activating proteins, and hormones (e.g., molecular determinants PRDM16 and BMP7). The transdifferentiation of WAT into BAT could be achieved by enhancing Prdm16 expression. These aspects of adipose tissue management represent exciting new approaches for treatment or prevention of obesity and topical body fat-related consumer-perceived imperfections.³

Tracing lineage of adipocytes to the origin of fat in the human body, a model has been proposed that brown adipocytes originate from a precursor shared with skeletal muscle that expresses Myf5-Cre, while all white adipocytes originate from Myf5-negative precursors. The signaling between lineages—hence, its management—could affect body fat distribution.⁴ For example, recent work shows that FGF21 is a beige adipokine capable of promoting a brown fat-like thermogenic program in WAT, which provides metabolic benefits of the transformation of WAT into BAT.⁵

Managing Fat: Where It Is (Or Isn’t)?
The regulation of biochemical signals that control formation, distribution, storage and utilization of body fat could lead to its removal where it is in excess and deposition where it is deficient. Skin wrinkles, for example, could be reduced by boosting size and/or number of dermal deposits of WAT. The transformation of WAT into BAT could lead to visual streamlining of arms, thighs, abdomen and other parts of the body having unwarranted fat storage.

Defensive application of adipose management cosmetics starting at an earlier age can be preventive of future body fat related skin concerns. In an extension of this technology, the redirection of fat from fat-excess areas (such as arms, thigh, hips, abdomen, chin and eyelids) to fat-deficient areas to plump skin for wrinkle reduction or to augment body parts could lead to future cosmetic products. This article provides cosmetics product applications for this new, exciting technology.

Adipose Dynamics & Metabolic Health
The two types of adipose tissue in humans, WAT and BAT, have distinct developmental origins and functions. WAT regulates maintenance of whole-body energy homeostasis by storing triglycerides when energy is in surplus, releasing free fatty acids as fuel during energy shortage, and secreting adipokines that regulate lipid and glucose metabolism. The maintenance of the size of WAT is critically important. Excessive expansion of WAT size leads to obesity. The absence or abnormal distribution of WAT leads to lipodystrophy, leading to metabolic disorders. BAT is a thermogenic organ whose mass is inversely correlated with body mass index and age. Therapeutic approaches targeting adipose tissue have been shown to be effective in improving adipose-related metabolic disorders.⁶

Nature-Based Adipogenesis Management Ingredients
The management of adipogenesis via a plethora of biochemical pathways has been studied. Thermogenic and anti-droplet accumulation agents are forging new technologies for the development of exciting anti-adipogenesis cosmetics formulations.

Thermogenic Agents. The stimulation of thermogenesis for the management of adiposity is receiving attention by the pharmaceutical, nutraceutical and functional food industries. The thermogenic and fat-oxidizing potential of varied bioactive food ingredients such as methylxanthines, polyphenols, capsaicinoids/capsinoids, minerals, proteins/amino acids, carbohydrates/sugars and fats/fatty acids have been recognized. Mechanistically, the compositions with thermogenic and fat-oxidizing potential possess both sympathomimetic stimulatory activity and acetyl-coA carboxylase inhibitory properties, which are capable of targeting both skeletal muscle and brown adipose tissue. The thermogenic potential of products tested in humans so far ranges from 2-5% above daily energy expenditure. It is hoped that this thermogenic potential could be increased to 10-15% above daily energy expenditure, which would have a clinically significant impact on adipose management.⁷

Capsaicin is well recognized for its anti-adipose benefits. It acts by reducing energy intake, enhancing energy metabolism, decreasing serum triglycerides, and inhibiting adipogenesis via activation of the transient receptor potential cation channel subfamily V member 1 (TRPV1).⁸ However, topical applications of capsaicin have been limited due to its strong skin and mucous irritation properties and pungent taste. Non-irritating capsinoids have shown potential as inhibitors of fat accumulation in adipocytes.⁹ Nonivamide, a less pungent capsaicin analog, was recently found to reduce lipid accumulation.¹⁰

6-Gingerol, one of the pungent constituents of Zingiber zerumbet, has been found to suppress oil droplet accumulation and reduce the droplet size in a concentration and time-dependent manner.¹¹

Anti-Droplet Accumulation & Anti-Adipogenesis Agents. Phytochemicals are potential agents to inhibit differentiation of pre-adipocytes, stimulate lipolysis and induce apoptosis of existing adipocytes, thereby reducing the amount of adipose tissue. Flavonoids, stilbenoids, phenolic acids, alkaloids, vitamins and other compounds represent the most researched groups of phytochemicals showing their effect on adipogenesis. Phytochemicals such as epigallocatechin-3-gallate, genistein and resveratrol have been reported to reduce lipid accumulation and induce adipocyte apoptosis in vitro and reduce body weight and adipose tissues mass in animal models. However, any well-conducted clinical trials are still lacking.¹²

A number of plant-based anti-droplet accumulation agents have been reported: noteworthy of which are aristolochic acid, from Aristolochia manshuriensis, a Korean traditional medicinal herb that is distributed in Japan, China and Korea; licochalcone A, from the roots of Brassica rapa (turnip);  (-)-epigallocatechin-3-gallate, from the leaves of Camelia sinensis (tea plant); ceramicine B, from Chisocheton ceramicus, is known to be a source of hardwood timber and is distributed in tropical countries, including Malaysia, Indonesia, Brunei, Papua New Guinea, Philippines and Vietnam; foenumoside B, from Lysimachia foenum-graecum—an anti-inflammatory agent; (+)-fargesin, (+)-eudesmin, (+)-epimagnolin A and (+)-magnolin, from Magnolia denudata flowers; salicin and salicortin, from Populus balsamifera or Balsam poplar—a medicinal plant used by the natives of Canada; 3″-(E)-p-coumaroyl quercitrin, from Albizia julibrissin, used as a remedy for insomnia, amnesia, sore throat and contusions, is a native plant in Japan, China and Korea; (±)-p-synephrine and β-cryptoxanthin, from fruits of Citrus unshu or Citrus unshiu (Satsuma mandarin orange); capsaisin, capsiate and 9-oxooctadeca-10,12-dienoic acid, from Capsicum annuum, more commonly known as paprika or red pepper; berberine, from Coptis chinensis or Coptis japonica, commonly known as Huanglian in China, Ouren in Japan or Hwangryunhaedok-tang in Korea; and curcumin, demethoxycurcumin and bisdemethoxycurcumin, from Curcuma longa, more commonly known as turmeric.¹³

The adipose-reducing property of oat is well known in dietary circles. In a recent study, glucosyl-derivatized oat extract prepared proteolytically from oat whole-grain was found to suppress adipogenesis-associated lipid-droplet accumulation.¹⁴

Recently, seaweeds rich in flavonoids and polysaccharides have shown the ability to modulate adiposity. Fucoxanthin, derived from brown seaweeds, has shown anti-adipose capability through modulating the elevation of ROS, and down-regulation of lipid metabolism genes. Fucosterol, obtained from brown algae Ecklonia stolonifera, resulted in a decrease of lipid accumulation in 3T3-L1 pre-adipocytes. Phlorotannins (phloroglucinol, eckol, dieckol, dioxinodehydroeckol and phlorofucofuroeckol A), isolated from Ecklonia stolonifera, were noted to inhibit lipid accumulation in 3T3-L1 cells without affecting cell viability. These phlorotannins also significantly reduced the expression levels of several adipocyte marker genes.¹⁵

In a study designed to investigate the effects of Trigonella foenum graecum (fenugreek) on adipogenesis and lipolysis, ethanolic extract of fenugreek seeds led to a significant reduction in lipid droplet accumulation. Trigonelline, a natural alkaloid found in fenugreek, is known to inhibit adipogenesis by its influences on the expression of peroxisome proliferator-activated receptor (PPARγ), which leads to subsequent down regulation of PPAR-γ mediated pathway during adipogenesis.¹⁶

In a recent study, 2,4,5-trimethoxybenzaldehyde, a bitter principle in plants and a cyclooxygenase II (COX-2) inhibitor, suppressed the differentiation of pre-adipocytes into adipocytes at the concentration of 0.5 mM. This suppression of adipogenesis was noted to occur through the regulation of extracellular signal-regulated kinase (ERK) phosphorylation.¹⁷ In fully differentiated adipocytes, 2,4,5,-trimethoxybenzaldehyde significantly decreased lipid accumulation by increasing the hydrolysis of triglycerides through suppression of perilipin A (lipid droplet coating protein) and up-regulation of hormone-sensitive lipase.¹⁸

Resveratrol has been reported to decrease adipogenesis in maturing pre-adipocytes. This action proceeded via down-regulating adipocyte specific transcription factors, enzymes and genes that modulate mitochondrial function. Additionally, resveratrol increased lipolysis and reduced lipogenesis in mature adipocytes, and grape skin extract reduced both adipo- and lipogenesis.¹⁹

1β-Hydroxy-2-oxopomolic acid, isolated from Agrimonia pilosa, has been reported to inhibit adipocyte differentiation and expression of several adipogenic marker genes, such as peroxisome proliferator activated receptor γ (PPARγ), CCAAT-enhancer-binding protein α (C/EBPα), glucose transporter 4 (GLUT4), adiponectin, adipocyte fatty acid-binding protein 2 (aP2), adipocyte determination and differentiation factor 1/sterol regulatory element binding protein 1c (ADD1/SREBP1c), resistin and fatty acid synthase (Fas) in pre-adipocytes.²⁰

Lupenone, isolated from Adenophora triphylla, has been shown to inhibit adipocyte differentiation and expression of adipogenic marker genes through down-regulation of related transcription factors, particularly the PPARγ gene.²¹

Soyasaponins Aa and Ab have been found to inhibit the accumulation of lipids and the expression of adiponectin, adipocyte determination and differentiation factor 1/sterol regulatory element binding protein 1c, adipocyte fatty acid-binding protein 2, fatty acid synthase and resistin in 3T3-L1 adipocytes. In addition, soyasaponins Aa and Ab suppressed the transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ).²²

Centipede grass, originating from China and South America, contains several C-glycosyl flavones and phenolic constituents including maysin and luteolinexerts. It has been found to possess anti-adipogenic activity by inhibiting the expression of C/EBPβ, C/EBPα, and PPARγ and the Akt signaling pathway in 3T3-L1 adipocytes.²³

Polygonum cuspidatum extract has been shown to inhibit pancreatic lipase activity and adipogenesis via attenuation of lipid droplet accumulation.²⁴

Dioxinodehydroeckol, isolated from Ecklonia cava, has been investigated for its inhibition of the differentiation of pre-adipocytes into adipocytes through the activation and modulation of the AMPK signaling pathway.²⁵

Baicalin, a flavonoid derived from the root of Scutellaria baicalensis, has exhibited a broad spectrum of biological activities including anti-adipogenesis; the latter involves down-regulation of major transcription factors in 3T3-L1 adipocyte differentiation including PPAR-γ, C/EBP-β and C/EBP-α through the down-regulation of PDK1/Akt phosphorylation.²⁶

Kirenol, a natural diterpenoid compound, has been reported to possess antioxidant, anti-inflammatory, anti-allergic and anti-arthritic activities. Recent work has shown that kirenol inhibits the differentiation and lipogenesis of adipocytes through the activation of the Wnt/β-catenin signaling pathway.²⁷

Carnosic acid, from Rosmarinus officinalis, and apigenin, isolated from Daphne genkwa, have been shown to inhibit pre-adipocytes differentiation by interfering with mitotic clonal expansion.²⁸

Dehydrodiconiferyl alcohol, isolated from Cucurbita moschata, has shown anti-adipogenic and anti-lipogenic effects.²⁹

Piperine, a component of black pepper, has been found to inhibit adipogenesis by antagonizing PPARγ activity in pre-adipocyte cells.³⁰

(+)-Episesamin, extracted from Japanese spice bush Lindera obtusiloba, has been reported to inhibit adipogenesis in pre-adipocytes by down-regulation of PPARγ and induction of iNOS.³¹

The extract of Alpinia officinarum has been reported to inhibit adipocyte differentiation through regulation of adipogenesis and lipogenesis.³²

Platycodin D, a saponin isolated from the root of Platycodon grandiflorum, has shown inhibition of lipogenesis through AMPKα-PPARγ2 in pre-adipocyte and modulation of fat accumulation.³³

Ursolic acid, a triterpenoid compound, has been shown to inhibit both pre-adipocyte differentiation and adipogenesis through the LKB1/AMPK pathway.³⁴

Conclusion
The number of scientifically driven topical ingredients for body sculpting and adipose management is quickly growing. However, consumers remain skeptical if anti-cellulite products are truly able to deliver non-illusory, sustainable results.

For brands to successfully market body sculpting and anti-cellulite products with new adipose management technologies they must tap into the highly effective “year round” sunscreen and anti-age skin care marketing strategies. Consumers went from wearing sunscreen solely to avoid a sunburn from extended time outside to daily wear, protecting skin against UV-induced free radical damage to skin cells. In addition, in a matter of just a few years, consumers went from moisturizing skin with non-descript creams to products immersed with anti-aging ingredients that help to repair and prevent future signs and biology of skin aging.

In order to disrupt the marketing narrative regarding anti-cellulite products, brands must educate the consumer about the necessity of preventive, long-term adipose exposure that goes far beyond spot-treating cellulite for summer celebrations by the pool or beach. By creating a cellulite product with multifunctional adipose management, moisturizing and anti-aging ingredient perspectives, a brand will be highly successful at selling the consumer on the importance of daily, year-round use of new generation anti-cellulite products.  

In the new-era of “preventive strikes against cellulite genesis,” adipose management ingredients and products are the future-wave for all cellulite and lipo-fill products, and a far cry from ubiquitous quick-fix cellulite and anti-aging body lotions. 

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John Stanek is manager of new technologies and product development at CoValence Laboratories; his primary responsibility is to research new technologies leading to new product concepts. He can be reached at jstanek@covalence.com.

Melinda Wochner is the chief marketing officer at CoValence Laboratories. She has worn many hats over her 20+ years at CoValence, but her primary responsibilities are to oversee the company’s website, press page, social media campaigns, tradeshows, creative and industry writing, private label products, in addition to being a member of the AZ District Export Council. She can be reached at melinda@covalence.com. For more information: http://covalence.com.

Shyam Gupta is an international consultant in innovative skin and hair care ingredients and delivery systems with 100+ patents, patent applications, cosmetics publications and book chapters specializing in nature and science based formulations with enhanced efficacy and consumer-appreciated performance attributes. He can be reached at shyam@biodermresearch.com. For more information: http://biodermresearch.com.

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