the MOUSE
Bones don't lie, Mosley. See you in Animal Park
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Some desire fat loss on particular regions. This could maybe be something for that.
There are several nano-carriers that can enhance the penetration of retinoids into the skin. Liposomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and polymeric nanoparticles are some examples. Liposomes, for instance, are lipid vesicles that can encapsulate retinoids and deliver them effectively into the skin layers. Similarly, SLNs and NLCs consist of solid lipids or a blend of solid and liquid lipids, respectively, which can encapsulate retinoids and improve their penetration. Polymeric nanoparticles utilize biocompatible polymers to encapsulate retinoids and facilitate their penetration into the skin. Choosing the appropriate nano-carrier depends on factors such as the desired depth of penetration, stability of the formulation, and skin compatibility.
Some of the science behind tretinoin and potential facial fat loss
Studies show that all trans-retinoic acid (ATRA) leads to lipid (fat) loss, and decreases pre-adipocyte differentiation (new fat cells trying to form) (1, 2, 11). This occurs when ATRA directly interacts with the fat cells, which can only happen in a lab, or when RA is ingested orally, or injected subcutaneously. The following post will explain why topical application causing fat loss is extremely unlikely.
Many factors influence if retinoids can travel through the skin layers to the fat tissues in the face. Regarding the formulation, it will depend on the particular retinoids in the formula, and the carrier being used. Most of the cells the retinoid molecules passes will interact with it in some way, and almost all of those retinoid molecules either get stuck in the stratum corneum or get involved in chemical reactions along the way. Excess retinoids run out long before they can reach the fat layer.
So how deep do retinoids actually penetrate the skin? Can they reach the fat tissue layer?
The average depth of facial skin (dermis + epidermis) ranges from ~0.8 mm (upper eyelid) to ~2.0 mm (lower nasal sidewall) (3, Table 1), in range with another study (4, Table 1b).
Pig skin and human skin are very similar and are often compared in topical studies. This study was performed on a 15 mm diameter by ~0.7 mm thick circular piece of dead pig skin, using two different nanocarriers. After application of 500 micrograms of retinol, up to 4 micrograms of retinol were found in the skin sample, almost all within the first 0.3 mm of skin (5, Fig. 1). Around 0.25 micrograms were found beyond 0.5 mm in residual dermis and subcutaneous fat cells (5). Compared to the natural amounts of RA already stored in those fat cells (12), the minuscule amount that travels there is a drop in the bucket. And keep in mind how thick our skin is in comparison.
Proretinal nanoparticles penetrated nearly 0.5 mm into the skin through hair follicles (10). These studies support the evidence that most of the retinoid gets trapped in the stratum corneum layer due to its lipophilic nature (8 Table 2, 9, 10).
Related question that came up during my search: can retinoids improve cellulite?
Yes, by increasing the thickness of the skin through increased collagen production and other well known benefits (6, 7). There is no evidence suggesting it impacts the fat cells, it just improves the elasticity and firmness of the skin, reducing the appearance of cellulite.
**Tldr** Yes, when introduced to cells in a lab or ingested orally, retinoids can cause fat loss. However, there is a lot of evidence showing that topical retinoids aren’t able to move much further than ~0.5 mm into the skin with the best nanocarriers, and even our thinnest area (upper eyelid) is ~0.8 mm thick. Almost all of the retinoid molecules get stuck/used in the first 0.3 mm. So it’s extremely unlikely that topical retinoid are capable of causing facial fat loss.
If you are elderly and/or have abnormally thin skin, there is a risk that a fraction (~5%) of the retinoid could enter the fatty tissue layer and cause facial fat loss. It’s impossible to quantify how much fat loss could occur. In my opinion, with everything I’ve put together, the risk is very minimal for the average user. See comments for more intricacies and sources. You can minimize penetration depth by choosing a less efficient carrier, like the cream based formula. Nanocarriers will increase depth.
Please feel free to ask further questions or probe into my sources. This is all still just scratching the surface of how complicated retinoic acid mechanisms can be.
References
1. [Stoecker, K., et al. Inhibition of fat cell differentiation in 3T3-L1 pre-adipocytes by all-trans retinoic acid: Integrative analysis of transcriptomic and phenotypic data. 2016.](https://www.sciencedirect.com/science/article/pii/S2214753516300341#bib0035)
2. [Berry, D. C. & Noy, N. All-trans-Retinoic Acid Represses Obesity and Insulin Resistance by Activating both Peroxisome Proliferation-Activated Receptor β/δ and Retinoic Acid Receptor. 2009](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698724/#__ffn_sectitle)
3. [Chopra, K., et al. A Comprehensive Examination of Topographic Thickness of Skin in the Human Face. 2015](https://academic.oup.com/asj/article/35/8/1007/249004)
4. [Chirikhina, E., et al. In Vivo Assessment of Water Content, Trans-Epidermial Water Loss and Thickness in Human Facial Skin. 2020](https://mdpi-res.com/d_attachment/applsci/applsci-10-06139/article_deploy/applsci-10-06139-v2.pdf?version=1599215152)
5. [Jenning, V., et al. Vitamin A loaded solid lipid nanoparticles for topical use: occlusive properties and drug targeting to the upper skin. 1999](https://www.sciencedirect.com/science/article/pii/S0939641199000752)
6. [Kligman, A., et al. Topical retinol improves cellulite. 1998.](https://www.tandfonline.com/doi/abs/10.3109/09546639909056013)
7. [Piérard-Franchimont, C, et al. A Randomized, Placebo-Controlled Trial of Topical Retinol in the Treatment of Cellulite. 2000](https://link.springer.com/article/10.2165/00128071-200001060-00005)
8. [Lehman, P.A., et al. Percutaneous absorption of retinoids: influence of vehicle, light exposure, and dose. 1988.](https://pdf.sciencedirectassets.com/271007/1-s2.0-S0022202X00X00851/1-s2.0-S0022202X88918155/main.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjEL7%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJHMEUCIQC03FwlFpfF7aeTH3pFbQSz4dDSW%2Bgb1tX4hOF2b7KvMAIgb46OKDK7k4y8v340CuAAHultuiaLXRwgkpQ0aed%2BfDYq2wQI5%2F%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FARAEGgwwNTkwMDM1NDY4NjUiDDivYLE84a7Xfs37ryqvBO0P27Xy3eX7FsxNLAMtrC9TPlklQk8PWtAC4E4TMWsyfv5cQkOgDlkzVYbUgnoT3W3KFtNqYVtp%2F%2B6byVsGS3VWp%2BvDknK8k341Y7lTd4Tyu7nmQ0paJLshxONobGSWcof6GkRQF0D56aJw85eTZL58ccTDf%2B%2BPRO0fJ97eJ7s2mLGGWpzemLqubx1wFeuVJZVMlnP9FNuIJJvmIKnh9f9rSXy78majKDjfvbPomXlmUe%2B2ZI1eRPdFJEkeIrKgCHA2i14Y1xerewZkuPzPg%2Bz8p%2BW7qsGyTGPQazUKG0Sun7i%2FHERDULMgr0sy9V8SPtdNuwS1lqIyiQPXqJpuBappZUvEEftnehSJU5m8OW8nmwETw9pm1cDtYRNz2yXs%2BdAJ6QPn1wMG2vydNVuPyiqnkt%2FRad2tq3n9gXqfD8ruyZFWl1b9K48BTlXnHYuphmkiYrM8U%2FmP15O6ZsyZwKrASor5Yq1DNPugCmSPP3PmPoJlMqTKQcD33cUB5B9wrW5ail%2BvITvDzJYf0lkuG2vmx39s%2Fo8qSyTDoYQU%2FH%2FnnrZB5es4tRzlyBxj0mk%2BVXyOCKL1OKlK5aCmo3RQKI4PdmSXL%2BxUjdSZDdfUW5H37z0KUta9d%2FFW7fYdiU%2BzIgEXKFvcOwnOa%2BDSvQjI2JBxKUYMe25avOiHICT0bNmh8IWqQqs1ad1VyVtB4040iXMOuStL2%2FUegEEs%2FFxyuseCBikmKe524bs43qKUTtcwz%2F6elgY6qQEm3%2BSUOOC9URBxRD252WNkU1FVw3nvf%2B%2BbU4auvvxLyTL%2F%2BJdaVL3UdFKW%2BwvMcztKV2dZr1EWiyG3rzF0rJuq4iyAyk18sEQzlh1xYBwNHZyijJILggLdJ8YR31hvhXVmbL7vdelUKFZVOnrKGvi3CygpA%2FOk2d3%2BWoREkHGNX%2BJYe3H8Px%2FFR1dGG9iY00lA0eGa7BnmlbNCCkZ6%2FZUm%2FLaMpaCW%2BTKL&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20220708T064221Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTY6OYMIUQA%2F20220708%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=27c1e1d61f758023285c16ca3c5e71f72a8fa0a369e17629a53a70fb219a9eb0&hash=d45c0999fbd84d5504f434b356e4506883713dd7225d914f6d03d5108e81787d&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0022202X88918155&tid=spdf-ec958058-77b4-46d1-bb44-0a371b1d75e8&sid=2ada5e60798116402c28eb58c48f5f5c5072gxrqa&type=client&ua=4d57515905590b515504&rr=7276d6e46e8b30bf)
9. [Masini, V., et al. Cutaneous bioavailability in hairless rats of tretinoin in liposomes or gel. 1993.](https://pubmed.ncbi.nlm.nih.gov/8429486/) *full text available
10. [Limcharoen, B., et al. Increasing the percutaneous absorption and follicular penetration of retinal by topical application of proretinal nanoparticles. 2019.](https://www.sciencedirect.com/science/article/pii/S0939641119301845#b0065)
11. [Machinal-Quélin, F., et al. Expression studies of key adipogenic transcriptional factors reveal that the anti-adipogenic properties of retinol in primary cultured human preadipocytes are due to retinol per se. 2001.](https://pubmed.ncbi.nlm.nih.gov/18498477/)
12. [Perumal, J., et al. Retinoic acid is abundantly detected in different depots of adipose tissue by SERS. 2016.](https://www.tandfonline.com/doi/full/10.1080/21623945.2016.1245817)
13. [Branchet, M.C., et al. Skin Thickness Changes in Normal Aging Skin. 1990.](https://www.karger.com/Article/Abstract/213172) *only abstract available
14. [Waller, J.M., et al. Review: Age and skin structure and function, a quantitative approach (I): blood flow, pH, thickness, and ultrasound echogenicity. 2005.](https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/j.0909-725X.2005.00151.x) *Reference 32, unavailable online
15. [Hirobe, S., et al. Clinical study of a retinoic acid-loaded microneedle patch for seborrheic keratosis or senile lentigo. 2017.](https://www.sciencedirect.com/science/article/pii/S0024320515301442#bb0115)
16. [Ziouzenkova, O., et al. Retinaldehyde represses adipogenesis and diet-induced obesity. 2007.](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2233696/)
There are several nano-carriers that can enhance the penetration of retinoids into the skin. Liposomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and polymeric nanoparticles are some examples. Liposomes, for instance, are lipid vesicles that can encapsulate retinoids and deliver them effectively into the skin layers. Similarly, SLNs and NLCs consist of solid lipids or a blend of solid and liquid lipids, respectively, which can encapsulate retinoids and improve their penetration. Polymeric nanoparticles utilize biocompatible polymers to encapsulate retinoids and facilitate their penetration into the skin. Choosing the appropriate nano-carrier depends on factors such as the desired depth of penetration, stability of the formulation, and skin compatibility.
Some of the science behind tretinoin and potential facial fat loss
Studies show that all trans-retinoic acid (ATRA) leads to lipid (fat) loss, and decreases pre-adipocyte differentiation (new fat cells trying to form) (1, 2, 11). This occurs when ATRA directly interacts with the fat cells, which can only happen in a lab, or when RA is ingested orally, or injected subcutaneously. The following post will explain why topical application causing fat loss is extremely unlikely.
Many factors influence if retinoids can travel through the skin layers to the fat tissues in the face. Regarding the formulation, it will depend on the particular retinoids in the formula, and the carrier being used. Most of the cells the retinoid molecules passes will interact with it in some way, and almost all of those retinoid molecules either get stuck in the stratum corneum or get involved in chemical reactions along the way. Excess retinoids run out long before they can reach the fat layer.
So how deep do retinoids actually penetrate the skin? Can they reach the fat tissue layer?
The average depth of facial skin (dermis + epidermis) ranges from ~0.8 mm (upper eyelid) to ~2.0 mm (lower nasal sidewall) (3, Table 1), in range with another study (4, Table 1b).
Pig skin and human skin are very similar and are often compared in topical studies. This study was performed on a 15 mm diameter by ~0.7 mm thick circular piece of dead pig skin, using two different nanocarriers. After application of 500 micrograms of retinol, up to 4 micrograms of retinol were found in the skin sample, almost all within the first 0.3 mm of skin (5, Fig. 1). Around 0.25 micrograms were found beyond 0.5 mm in residual dermis and subcutaneous fat cells (5). Compared to the natural amounts of RA already stored in those fat cells (12), the minuscule amount that travels there is a drop in the bucket. And keep in mind how thick our skin is in comparison.
Proretinal nanoparticles penetrated nearly 0.5 mm into the skin through hair follicles (10). These studies support the evidence that most of the retinoid gets trapped in the stratum corneum layer due to its lipophilic nature (8 Table 2, 9, 10).
Related question that came up during my search: can retinoids improve cellulite?
Yes, by increasing the thickness of the skin through increased collagen production and other well known benefits (6, 7). There is no evidence suggesting it impacts the fat cells, it just improves the elasticity and firmness of the skin, reducing the appearance of cellulite.
**Tldr** Yes, when introduced to cells in a lab or ingested orally, retinoids can cause fat loss. However, there is a lot of evidence showing that topical retinoids aren’t able to move much further than ~0.5 mm into the skin with the best nanocarriers, and even our thinnest area (upper eyelid) is ~0.8 mm thick. Almost all of the retinoid molecules get stuck/used in the first 0.3 mm. So it’s extremely unlikely that topical retinoid are capable of causing facial fat loss.
If you are elderly and/or have abnormally thin skin, there is a risk that a fraction (~5%) of the retinoid could enter the fatty tissue layer and cause facial fat loss. It’s impossible to quantify how much fat loss could occur. In my opinion, with everything I’ve put together, the risk is very minimal for the average user. See comments for more intricacies and sources. You can minimize penetration depth by choosing a less efficient carrier, like the cream based formula. Nanocarriers will increase depth.
Please feel free to ask further questions or probe into my sources. This is all still just scratching the surface of how complicated retinoic acid mechanisms can be.
References
1. [Stoecker, K., et al. Inhibition of fat cell differentiation in 3T3-L1 pre-adipocytes by all-trans retinoic acid: Integrative analysis of transcriptomic and phenotypic data. 2016.](https://www.sciencedirect.com/science/article/pii/S2214753516300341#bib0035)
2. [Berry, D. C. & Noy, N. All-trans-Retinoic Acid Represses Obesity and Insulin Resistance by Activating both Peroxisome Proliferation-Activated Receptor β/δ and Retinoic Acid Receptor. 2009](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698724/#__ffn_sectitle)
3. [Chopra, K., et al. A Comprehensive Examination of Topographic Thickness of Skin in the Human Face. 2015](https://academic.oup.com/asj/article/35/8/1007/249004)
4. [Chirikhina, E., et al. In Vivo Assessment of Water Content, Trans-Epidermial Water Loss and Thickness in Human Facial Skin. 2020](https://mdpi-res.com/d_attachment/applsci/applsci-10-06139/article_deploy/applsci-10-06139-v2.pdf?version=1599215152)
5. [Jenning, V., et al. Vitamin A loaded solid lipid nanoparticles for topical use: occlusive properties and drug targeting to the upper skin. 1999](https://www.sciencedirect.com/science/article/pii/S0939641199000752)
6. [Kligman, A., et al. Topical retinol improves cellulite. 1998.](https://www.tandfonline.com/doi/abs/10.3109/09546639909056013)
7. [Piérard-Franchimont, C, et al. A Randomized, Placebo-Controlled Trial of Topical Retinol in the Treatment of Cellulite. 2000](https://link.springer.com/article/10.2165/00128071-200001060-00005)
8. [Lehman, P.A., et al. Percutaneous absorption of retinoids: influence of vehicle, light exposure, and dose. 1988.](https://pdf.sciencedirectassets.com/271007/1-s2.0-S0022202X00X00851/1-s2.0-S0022202X88918155/main.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjEL7%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJHMEUCIQC03FwlFpfF7aeTH3pFbQSz4dDSW%2Bgb1tX4hOF2b7KvMAIgb46OKDK7k4y8v340CuAAHultuiaLXRwgkpQ0aed%2BfDYq2wQI5%2F%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FARAEGgwwNTkwMDM1NDY4NjUiDDivYLE84a7Xfs37ryqvBO0P27Xy3eX7FsxNLAMtrC9TPlklQk8PWtAC4E4TMWsyfv5cQkOgDlkzVYbUgnoT3W3KFtNqYVtp%2F%2B6byVsGS3VWp%2BvDknK8k341Y7lTd4Tyu7nmQ0paJLshxONobGSWcof6GkRQF0D56aJw85eTZL58ccTDf%2B%2BPRO0fJ97eJ7s2mLGGWpzemLqubx1wFeuVJZVMlnP9FNuIJJvmIKnh9f9rSXy78majKDjfvbPomXlmUe%2B2ZI1eRPdFJEkeIrKgCHA2i14Y1xerewZkuPzPg%2Bz8p%2BW7qsGyTGPQazUKG0Sun7i%2FHERDULMgr0sy9V8SPtdNuwS1lqIyiQPXqJpuBappZUvEEftnehSJU5m8OW8nmwETw9pm1cDtYRNz2yXs%2BdAJ6QPn1wMG2vydNVuPyiqnkt%2FRad2tq3n9gXqfD8ruyZFWl1b9K48BTlXnHYuphmkiYrM8U%2FmP15O6ZsyZwKrASor5Yq1DNPugCmSPP3PmPoJlMqTKQcD33cUB5B9wrW5ail%2BvITvDzJYf0lkuG2vmx39s%2Fo8qSyTDoYQU%2FH%2FnnrZB5es4tRzlyBxj0mk%2BVXyOCKL1OKlK5aCmo3RQKI4PdmSXL%2BxUjdSZDdfUW5H37z0KUta9d%2FFW7fYdiU%2BzIgEXKFvcOwnOa%2BDSvQjI2JBxKUYMe25avOiHICT0bNmh8IWqQqs1ad1VyVtB4040iXMOuStL2%2FUegEEs%2FFxyuseCBikmKe524bs43qKUTtcwz%2F6elgY6qQEm3%2BSUOOC9URBxRD252WNkU1FVw3nvf%2B%2BbU4auvvxLyTL%2F%2BJdaVL3UdFKW%2BwvMcztKV2dZr1EWiyG3rzF0rJuq4iyAyk18sEQzlh1xYBwNHZyijJILggLdJ8YR31hvhXVmbL7vdelUKFZVOnrKGvi3CygpA%2FOk2d3%2BWoREkHGNX%2BJYe3H8Px%2FFR1dGG9iY00lA0eGa7BnmlbNCCkZ6%2FZUm%2FLaMpaCW%2BTKL&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20220708T064221Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTY6OYMIUQA%2F20220708%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=27c1e1d61f758023285c16ca3c5e71f72a8fa0a369e17629a53a70fb219a9eb0&hash=d45c0999fbd84d5504f434b356e4506883713dd7225d914f6d03d5108e81787d&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0022202X88918155&tid=spdf-ec958058-77b4-46d1-bb44-0a371b1d75e8&sid=2ada5e60798116402c28eb58c48f5f5c5072gxrqa&type=client&ua=4d57515905590b515504&rr=7276d6e46e8b30bf)
9. [Masini, V., et al. Cutaneous bioavailability in hairless rats of tretinoin in liposomes or gel. 1993.](https://pubmed.ncbi.nlm.nih.gov/8429486/) *full text available
10. [Limcharoen, B., et al. Increasing the percutaneous absorption and follicular penetration of retinal by topical application of proretinal nanoparticles. 2019.](https://www.sciencedirect.com/science/article/pii/S0939641119301845#b0065)
11. [Machinal-Quélin, F., et al. Expression studies of key adipogenic transcriptional factors reveal that the anti-adipogenic properties of retinol in primary cultured human preadipocytes are due to retinol per se. 2001.](https://pubmed.ncbi.nlm.nih.gov/18498477/)
12. [Perumal, J., et al. Retinoic acid is abundantly detected in different depots of adipose tissue by SERS. 2016.](https://www.tandfonline.com/doi/full/10.1080/21623945.2016.1245817)
13. [Branchet, M.C., et al. Skin Thickness Changes in Normal Aging Skin. 1990.](https://www.karger.com/Article/Abstract/213172) *only abstract available
14. [Waller, J.M., et al. Review: Age and skin structure and function, a quantitative approach (I): blood flow, pH, thickness, and ultrasound echogenicity. 2005.](https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/j.0909-725X.2005.00151.x) *Reference 32, unavailable online
15. [Hirobe, S., et al. Clinical study of a retinoic acid-loaded microneedle patch for seborrheic keratosis or senile lentigo. 2017.](https://www.sciencedirect.com/science/article/pii/S0024320515301442#bb0115)
16. [Ziouzenkova, O., et al. Retinaldehyde represses adipogenesis and diet-induced obesity. 2007.](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2233696/)
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