Author: Dhruv Parikh, 2027
Editor: El Herbert, 2024
There is adipose (fat) tissue deposited throughout the human body composed of different types of adipocytes, or fat cells. Though fats are generally looked down upon as the source of obesity, diabetes, cardiac diseases, and other comorbidities, it is important to distinguish that our body contains different types of fat; tissue. Some of these fat tissues are helpful and can be utilized to combat the aforementioned health issues. Adipose tissue has been described by researchers as an “endocrine organ with high metabolic activity” host to a complex interplay of hormones and cellular mechanisms that contribute to the tissue metabolism as well as the whole human body [1].
White adipose tissue (WAT) is light yellow in color and has less access to nerves and blood vessels. WAT generates large quantities of peptides and lipids, known as adipokines and lipokines respectively, which are known to play a role in the secretion of metabolism-regulating hormones. Two adipokines, leptin and adiponectin, are related to obesity and diabetes, respectively, as deviations from normal levels can impact risk of these diseases [1]. WAT mainly is used as a form of energy storage; however, expansion of WAT tissue is a significant contributor to obesity [2]. Exercise and energy expenditure have been associated with regulation of WAT levels. Though the link to obesity may put WAT in a negative light, the human body still needs certain levels of WAT to store energy and insulate our organs.
Brown adipose tissue (BAT) is brown in color due to an increased number of mitochondria. Rather than originating from white adipocytes, BAT is produced from muscle tissue precursor cells [1].
Mitochondria are colloquially referred to as the “powerhouse of the cell.” This is true as mitochondria are responsible for generating the energy needed within the cell. In BAT, mitochondria have a unique protein, called uncoupling protein 1 (UCP1) which allows them to release energy directly as heat which significantly increases energy consumption by BAT [3, 4]. UCP1 activates in response to stimuli from cold temperature as a way to produce heat without making the body physically shiver to do so, hence the technical name for the process: non-shivering thermogenesis (NST) [4, 5].
Researchers are studying thermogenesis mechanisms to develop treatments for obesity, diabetes, and other related conditions. Activation of thermogenesis in BAT is controlled by the nervous system. The sympathetic nervous system (SNS) and temperature-based stimuli received by skin neurons cause the release of several neurotransmitters from the brain to receptors on BAT, promoting UCP1 activity. The interplay between the nervous and endocrine system and BAT impacts the thyroid as well. Thyroid hormone T3 is released into the bloodstream due to cold stimuli or presence of thyroid-stimulating hormones, which enhances the presence of UCP1 and subsequently thermogenesis. This has led to the hypothesis that impairment of BAT metabolism in hypothyroidism may contribute to overweight phenotypes and insulin resistance. Manipulation of thyroid hormones and BAT pathways are being investigated as treatments for obesity [4].
As mentioned before, the expansion and excess of WAT leads to obesity. This has spurred research on ways in which WAT can be BAT’s helpful characteristics to increase thermogenic capacity and help combat obesity and its comorbidities. In a process described as “browning,” white adipocytes are converted to beige or brite (brown-in-white) adipocytes which have similar thermogenic capabilities as BAT. Exercise has been associated with expression of PGC1α, a gene known to regulate several characteristics of brown and beige/brite adipocytes [4, 6, 7]. Mice with impaired PGC1α expression, have displayed continued function of BAT but can no longer cause browning of WAT [6]. Several of the aforementioned endocrine and SNS processes have been associated with browning of WAT such as binding of neurotransmitters to brown adipocyte receptors, release of the T3 hormone by the thyroid, and pathways associated with the functions of adipokines leptin and adiponectin [8]. In recent studies, scientists have genetically engineered human brown-like (HUMBLE) adipocytes which display similar thermogenic capacity as BAT due to UCP1 expression. The fusion of WAT and BAT genetics and metabolic mechanisms further highlights the importance of considering the browning process in combating obesity [9]. Together, white, brown, beige/brite, and the engineered HUMBLE fat can be used to design treatments at the genetic and protein-protein interaction level to increase UCP1-mediated thermogenesis and induce weight loss to minimize obesity and its comorbidities.
Other than weight loss drug development and genetic engineering of fat, many natural products and the gut microbiome are being studied as contributors to browning and thermogenesis. The natural products associated with browning come from several food sources, associating diet with obesity treatments. The list of natural products associated with browning includes but is not limited to: capsaicin found in chilies, tea polyphenols, ginsenoside Rb1/Rb2 found in ginseng, long chain fatty acids such as those in bitter melon seed oil, phenolic acids such as curcumin found in turmeric, and extracts from cinnamon and a handful of berry species [10]. If incorporated into a diet routine in conjunction with a proper exercise regimen, these natural products may promote browning and thermogenesis. Diet and nutrition are further associated with browning as the relation between intermittent fasting and the gut microbiome is being explored to see their effect on browning and controlling metabolic diseases. In a recent study from a joint collaboration between the NIH and Hunan Normal University, researchers collected data that an every-other-day-fasting (EODF) regimen may promote UCP1 expression and NST, which leads to browning in WAT. The diversity and quantity of gut microbiota, which can be significantly impacted by EODF, was also associated with the abilities of metabolic functions as “several indices of metabolic function were also decreased when the gut microbiota were depleted” [11]. Though studies have shown that BAT is not a significant contributor to total energy metabolism and may even pose a heightened cardiovascular risk due to overexertion of the heart to maintain the additional energy consumption, browning of WAT still may be helpful as a way to reverse the effects of WAT expansion on obesity [2,12].
Whether studies into adipose tissue metabolism continue as a treatment for obesity, diabetes, and other comorbidities or healthcare professionals as well as patients opt for newer semaglutide treatments such as Ozempic® or Wegovy®, learning about the human body and mechanisms of metabolism and thermogenesis is important as our bodies use these to maintain homeostasis and keep us alive [13]. Through the study of adipose tissue and its unique mechanisms, we can gain a better understanding of how our body regulates our temperature, insulates our organs, and tries to store nutrients for long-term usage.
References
[1] Frigolet, M. E., & Gutiérrez-Aguilar, R. (2020). The colors of adipose tissue. Gaceta de México, 156(2). https://doi.org/10.24875/gmm.m20000356
[2] White, U. (2023). Adipose tissue expansion in obesity, health, and disease. Frontiers in Cell and Developmental Biology, 11. https://doi.org/10.3389/fcell.2023.1188844
[3] Larson, C. M. (2019). Translational Pharmacology and Physiology of Brown Adipose Tissue in Human Disease and Treatment. Handbook of Experimental Pharmacology, 381–424. https://doi.org/10.1007/164_2018_184
[4] Broeders, E., Bouvy, N. D., & van Marken Lichtenbelt, W. D. (2014). Endogenous ways to stimulate brown adipose tissue in humans. Annals of Medicine, 47(2), 123–132. https://doi.org/10.3109/07853890.2013.874663
[5] Crichton, P. G., Lee, Y., & Kunji, E. R. S. (2017). The molecular features of uncoupling protein 1 support a conventional mitochondrial carrier-like mechanism. Biochimie, 134, 35–50. https://doi.org/10.1016/j.biochi.2016.12.016
[6] Cereijo, R., Giralt, M., & Villarroya, F. (2014). Thermogenic brown and beige/brite adipogenesis in humans. Annals of Medicine, 47(2), 169–177. https://doi.org/10.3109/07853890.2014.952328
[7] Jiang, N., Yang, M., Han, Y., Zhao, H., & Sun, L. (2022). PRDM16 Regulating Adipocyte Transformation and Thermogenesis: A Promising Therapeutic Target for Obesity and Diabetes. Frontiers in Pharmacology, 13. https://doi.org/10.3389/fphar.2022.870250
[8] Altınova, A. E. (2021). Beige Adipocyte as the Flame of White Adipose Tissue: Regulation of Browning and Impact of Obesity. The Journal of Clinical Endocrinology & Metabolism, 107(5). https://doi.org/10.1210/clinem/dgab921
[9] Wang, C.-H., Lundh, M., Fu, A., Kriszt, R., Huang, T. L., Lynes, M. D., Leiria, L. O., Shamsi, F., Darcy, J., Greenwood, B. P., Narain, N. R., Tolstikov, V., Smith, K. L., Emanuelli, B., Chang, Y.-T., Hagen, S., Danial, N. N., Kiebish, M. A., & Tseng, Y.-H. (2020). CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice. Science Translational Medicine, 12(558), eaaz8664. https://doi.org/10.1126/scitranslmed.aaz8664
[10] MA, P., HE, P., XU, C.-Y., HOU, B.-Y., QIANG, G.-F., & DU, G.-H. (2020). Recent developments in natural products for white adipose tissue browning. Chinese Journal of Natural Medicines, 18(11), 803–817. https://doi.org/10.1016/S1875-5364(20)60021-8
[11] Li, G., Xie, C., Lu, S., Nichols, R. G., Tian, Y., Li, L., Patel, D., Ma, Y., Brocker, C. N., Yan, T., Krausz, K. W., Xiang, R., Gavrilova, O., Patterson, A. D., & Gonzalez, F. J. (2017). Intermittent Fasting Promotes White Adipose Browning and Decreases Obesity by Shaping the Gut Microbiota. Cell Metabolism, 26(4), 672-685.e4. https://doi.org/10.1016/j.cmet.2017.08.019
[12] Marlatt, K. L., & Ravussin, E. (2017). Brown Adipose Tissue: an Update on Recent Findings. Current Obesity Reports, 6(4), 389–396. https://doi.org/10.1007/s13679-017-0283-6
[13] Research, C. for D. E. and. (2023). Medications Containing Semaglutide Marketed for Type 2 Diabetes or Weight Loss. FDA. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/medications-containing-semaglutide-marketed-type-2-diabetes-or-weight-loss