The most pervasive epidemic across the United States today is not something that the occasional vaccination or hand-washing can prevent. It is not some foreign virus or juggernaut bacteria; in fact, it has been prevalent for decades and still does not garner the attention it deserves: that epidemic is none other than obesity. The CDC reports that 39.8% of US adults are obese, adding up to a whopping $147 billion of estimated annual medical cost nationally (Center for Disease Control and Prevention). On top of the medical costs of obesity is the associated susceptibility to cancer that many overweight adults face. With the projection that over 85% of American adults will be overweight by 2030, the statistic that over 20% of cancers are due to obesity now seems to loom larger than ever (Wang et al., 2008) (De Pergola 2013).
The scientific community has mounted great efforts to better understand this relationship. Studies examining the relationship between the two have found possible culprits: obesity-related inflammation and metabolic changes that occur in fat storage cells called adipocytes (Park et. al, 2014). Within this dynamic, cancer cells gain a significant advantage: components found in “fatty” environments change the metabolism in tumor cells that allows for their increased survival and motility, both key for the cancer’s success. One of this metabolic changes is called the Warburg Effect, in which cells switch their primary means of energy derivation from oxygen to the breakdown of glucose (Potter et al., 2016).
Metabolic switches in cancerous conditions don’t only apply to tumor cells. Natural killer cells, or the “military infantry” of the immune system that kills infected cells, are vital for both fighting everyday infections as well as anti-cancer responses. Like all cells, natural killer cells undergo metabolic changes to perform various functions. In the context of their anti-cancer response, NK cells happen to undergo the same metabolic switch as tumor cells, going from oxidative phosphorylation to glycolysis, a boost in energy enabling them to perform their cancer-killing function. NK cells use this energy to exocytose, or release, their toxic contents to specifically kill the target cell to which they are bound (Topham et al., 2009). In fact, recent research suggests that restriction of this glycolysis has a “profound effect” on NK anti-cancer functions, suggesting that NK cells are sensitive to -and dependent on- changes in their metabolism (Gardiner et al., 2017).
Upon the consideration that obesity yields a predisposition to cancer, the team of Xavier Michelet, Lydia Dyck, Lydia Lynch conducted a study investigating the effects of obesity directly as they apply to NK function and the development of cancer.
The authors’ first goal was to pinpoint exactly what effect obesity had on the function of NK cells. Looking for gene expression differences in mice on eight-week high fat diets (HFD) versus normal diets (SFD), the authors found shocking results. Out of the 3000 genes that HFD mice expressed differently than their lean counterparts, fatty acid-binding molecules were upregulated and molecules important for NK killing were downregulated. This initial result proposes a trade-off between NK cells ability to 'metabolize fat' and their ability to perform their normal killer functions. The study also found that the mice’s NK reaction to lipid-rich environments characteristic of obesity also applied to humans. As shown in the images below, human NK cells have higher lipid counts (Image 1) and lower granzyme production (Image 2) in obese individuals (shown in red) than in lean individuals (black).
Fig. 2: Obesity leads to NK cell loss of function and lipid accumulation.
The next step the authors took was to determine if this loss of NK function correlated with lipid accumulation was a causal relationship. To assess this, NK cells from lean individuals were grown alongside two types of fatty acids and were tested to see their effectiveness in cancer. The image below shows that untreated cells (black) yielded the highest killing percentage, whereas palmitate-cultured (red) and palmitate/oleate-cultured (orange) NK cells showed respective decreases in their ability to kill.
Fig. 3: Lipid uptake and accumulation leads to NK cell loss of function.
This discovery led the researchers to examine if that dysfunction is exacerbated by metabolic defects in NK cells. To do this, the researchers tested if there was a difference in ATP generation and glycolysis in obese versus lean humans. Notably, there was. Upon the “metabolic switch” of NK cells, cells in obese individuals had a lower metabolic response than lean individuals.
Finally, the focus was turned towards the NK cells ability to perform their anti-tumor functions. Zooming out of the molecular level, the researchers concluded the study by observing how lipid-filled NK cells responded to tumor growths. Predictably, NK cells with lipid accumulation resulted in a failure to reduce tumor growth, as shown in the figure below. This was the kicker: lipid-treated NK cells allowed for greater tumor volume than its non lipid-treated counterpart!
Overall, these authors were able to successfully interconnect the effects of obesity on NK cells with the well-studied fact that obesity is correlated with cancer. Being able to specify exactly how obesity-induced environments affect NK cells, how that environment impairs NK cell function, and how that impairment jeopardizes obese individuals’ ability to fight cancer can have far-reaching implications for cancer biology as well as anti-obesity efforts. Knowing that NK cells endure metabolic damage in heavy-lipid environments characteristic of obesity, to somehow recover this normal metabolism could offset the most frightening complications of obesity for which its patients are at risk. This study provided ample evidence that tumor-suppressor mechanisms are definitively impaired in obesity-induced molecular environments. This paper opens doors for a variety of future endeavors regarding the prevention and restoration of immune systems compromised by the effects of obesity. Everyone knows that staying healthy and leading active lives are in our best interest for our heart, but now we know that our heart isn’t the only thing put at risk for those who chronically overindulge.
Works cited:
1. Centers for Disease Control and Prevention. (2011). Overweight and Obesity. Retrieved from https://www.cdc.gov/obesity/index.html
2. De Pergola, Giovanni and Franco Silvestris. “Obesity as a major risk factor for cancer” Journal of obesity vol. 2013 (2013): 291546.
3. Doerstling SS, O'Flanagan CH, Hursting SD. Obesity and Cancer Metabolism: A Perspective on Interacting Tumor-Intrinsic and Extrinsic Factors. Front Oncol. 2017;7:216. Published 2017 Sep 14. doi:10.3389/fonc.2017.00216
4. Gardiner, Clair M and David K Finlay. “What Fuels Natural Killers? Metabolism and NK Cell Responses” Frontiers in immunology vol. 8 367. 3 Apr. 2017, doi:10.3389/fimmu.2017.00367
5. Michelet, Xavier, et al. “Metabolic Reprogramming of Natural Killer Cells in Obesity Limits Antitumor Responses.” Nature News, Nature Publishing Group, 12 Nov. 2018, www.nature.com/articles/s41590-018-0251-7.
6. Park, J., Morley, T. S., Kim, M., Clegg, D. J. & Scherer, P. E. Obesity and cancer mechanisms underlying tumour progression and recurrence. Nat. Rev. Endocrinol. 10, 455–465 (2014).
7. Potter M, Newport E, Morten KJ. The Warburg effect: 80 years on. Biochem Soc Trans. 2016;44(5):1499-1505.
8. Topham, Nicola J and Eric W Hewitt. “Natural killer cell cytotoxicity: how do they pull the trigger?” Immunology vol. 128,1 (2009): 7-15.
9. Wang, Y. , Beydoun, M. A., Liang, L. , Caballero, B. and Kumanyika, S. K. (2008), Will All Americans Become Overweight or Obese? Estimating the Progression and Cost of the US Obesity Epidemic. Obesity, 16: 2323-2330
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