Obesity explained episoeds 8 and 9 are out. They are based on a trio of really great papers that have come out since 2018. Two are in the journal Nature and one is in PNAS, but remarkably all three are publicly available. The papers are (Kim, 2018), (Kim, 2020) and (Huang, 2022).
Kim (2018) shows that the aryl hydrocarbon receptor (AhR) is activated by insulin signalling and translocates to the nucleus to initiate gene transcription after a meal. Later, it’s transcriptional activity is suppressed by bile acid signalling. Bile acids absorbed in the intestine post-prandially activate the FXR, which releases SHP which directly binds to and inactivates the AhR.
This finding turns our understanding of the AhR inside out. It was long thought that the AhR’s main role was to identify and metabolize toxins such as TCDD. This paper places the AhR directly at the center of our endogenous metabolism.
Furthermore, the paper goes on to show that when bile acid signalling breaks down, the AhR can run amock in the liver, leaving PEMT permanently active in the liver. This results in overproduction of phosphatidylcholine, which uses up methyl groups that are needed elsewhere, leading to fatty liver.
The paper further shows that bile acid signalling breaks down in humans with fatty liver, leading to upregulated PEMT.
Kim (2020) goes on to show that vitamin B12 and folate – two B vitamins involved in the methylation cycle – both actively bind to and inactivate the AhR. They show that, in fact, symptoms traditionally associated with folate and B12 deficiency – anemia, fatty liver and neural tube defects – can be caused by activating the AhR with TCDD and prevented with the small bits of B12 and folate that inhibit the AhR.
This puts the AhR at the center of the discussion of methylation and vitamin deficiency.
Lastly, Kim (2022 (different Kim)) shows that the development of obesity in both mice and humans is associated with low vitamin B6 levels. Low B6 leads to a buildup of the tryptophan metabolite kynurenine which is a well known activator of the AhR. The AhR upregulates IDO1 in adipose tissue, leading to more tryptohpan being converted to kynurenine, a positive feedback loop leading to fatness.
Three different approaches are used with varying effect to break mice given a fattening diet out of this feedback loop: adipose specific deletion of IDO1, adipose specific deletion of the AhR or vitamin B6 supplementation. Vitamin B6 supplementation turns out to be the best strategy!
This nexus of B vitamins and AhR biology give me a perfect platform to discuss traditional diets and the ancestral wisdom inherent in balancing B vitamin intake.
Here are the historical documents I’ve taken the data about traditional Diets from:
Cornell Extension Bulletin 478. “Living From The Farm.”
“Present Day Diets in the United States” by Hazel K. Stiebeling and Callie Mae Coons. From the 1939 USDA Yearbook of Agriculture
Please enjoy, “Turnip Greens and Buttermilk” and “Meat and Potatoes?”.
Appel, L. J., Miller, E. R., III, Jee, S. H., Stolzenberg-Solomon, R., RD, Lin, P.-H., Erlinger, T., Nadeau, M. R., & Selhub, J. (2000). Effect of Dietary Patterns on Serum Homocysteine. In Circulation (Vol. 102, Issue 8, pp. 852–857). Ovid Technologies (Wolters Kluwer Health). https://doi.org/10.1161/01.cir.102.8.852
Belobrajdic, D. P., McIntosh, G. H., & Owens, J. A. (2004). A High-Whey-Protein Diet Reduces Body Weight Gain and Alters Insulin Sensitivity Relative to Red Meat in Wistar Rats. In The Journal of Nutrition (Vol. 134, Issue 6, pp. 1454–1458). Elsevier BV. https://doi.org/10.1093/jn/134.6.1454
Brouwer-Brolsma, E., Dhonukshe-Rutten, R., van Wijngaarden, J., Zwaluw, N., Velde, N., & de Groot, L. (2015). Dietary Sources of Vitamin B-12 and Their Association with Vitamin B-12 Status Markers in Healthy Older Adults in the B-PROOF Study. In Nutrients (Vol. 7, Issue 9, pp. 7781–7797). MDPI AG. https://doi.org/10.3390/nu7095364
Carter, P., Gray, L. J., Troughton, J., Khunti, K., & Davies, M. J. (2010). Fruit and vegetable intake and incidence of type 2 diabetes mellitus: systematic review and meta-analysis. In BMJ (Vol. 341, Issue aug18 4, pp. c4229–c4229). BMJ. https://doi.org/10.1136/bmj.c4229
Casanueva, E., Drijanski, A., Fernández-Gaxiola, A. C., Meza, C., & Pfeffer, F. (2000). Folate deficiency is associated with obesity and anemia in Mexican urban women. In Nutrition Research (Vol. 20, Issue 10, pp. 1389–1394). Elsevier BV. https://doi.org/10.1016/s0271-5317(00)80020-2
da Silva, V. R., Hausman, D. B., Kauwell, G. P. A., Sokolow, A., Tackett, R. L., Rathbun, S. L., & Bailey, L. B. (2013). Obesity affects short-term folate pharmacokinetics in women of childbearing age. In International Journal of Obesity (Vol. 37, Issue 12, pp. 1608–1610). Springer Science and Business Media LLC. https://doi.org/10.1038/ijo.2013.41
Dhillon, V. S., Zabaras, D., Almond, T., Cavuoto, P., James-Martin, G., & Fenech, M. (2017). Whey protein isolate improves vitamin B12and folate status in elderly Australians with subclinical deficiency of vitamin B12. In Molecular Nutrition & Food Research (Vol. 61, Issue 5, p. 1600915). Wiley. https://doi.org/10.1002/mnfr.201600915
Elwood, P. C., Pickering, J. E., & Fehily, A. M. (2007). Milk and dairy consumption, diabetes and the metabolic syndrome: the Caerphilly prospective study. In Journal of Epidemiology & Community Health (Vol. 61, Issue 8, pp. 695–698). BMJ. https://doi.org/10.1136/jech.2006.053157
Hamer, D., & Herrero, S. (1987). Grizzly Bear Food and Habitat in the Front Ranges of Banff National Park, Alberta. In Bears: Their Biology and Management (Vol. 7, p. 199). JSTOR. https://doi.org/10.2307/3872626
Huang, T., Song, J., Gao, J. et al. Adipocyte-derived kynurenine promotes obesity and insulin resistance by activating the AhR/STAT3/IL-6 signaling. Nat Commun 13, 3489 (2022)
Kim, D. J., Venkataraman, A., Jain, P. C., Wiesler, E. P., DeBlasio, M., Klein, J., Tu, S. S., Lee, S., Medzhitov, R., & Iwasaki, A. (2020). Vitamin B12 and folic acid alleviate symptoms of nutritional deficiency by antagonizing aryl hydrocarbon receptor. In Proceedings of the National Academy of Sciences (Vol. 117, Issue 27, pp. 15837–15845). Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.2006949117
Kim, Y.-C., Seok, S., Byun, S., Kong, B., Zhang, Y., Guo, G., Xie, W., Ma, J., Kemper, B., & Kemper, J. K. (2018). AhR and SHP regulate phosphatidylcholine and S-adenosylmethionine levels in the one-carbon cycle. In Nature Communications (Vol. 9, Issue 1). Springer Science and Business Media LLC. https://doi.org/10.1038/s41467-018-03060-y
Rafiq, S., Huma, N., Pasha, I., Sameen, A., Mukhtar, O., & Khan, M. I. (2015). Chemical Composition, Nitrogen Fractions and Amino Acids Profile of Milk from Different Animal Species. In Asian-Australasian Journal of Animal Sciences (Vol. 29, Issue 7, pp. 1022–1028). Asian Australasian Association of Animal Production Societies. https://doi.org/10.5713/ajas.15.0452
Santaren, I. D., Watkins, S. M., Liese, A. D., Wagenknecht, L. E., Rewers, M. J., Haffner, S. M., Lorenzo, C., & Hanley, A. J. (2014). Serum pentadecanoic acid (15:0), a short-term marker of dairy food intake, is inversely associated with incident type 2 diabetes and its underlying disorders. In The American Journal of Clinical Nutrition (Vol. 100, Issue 6, pp. 1532–1540). Elsevier BV. https://doi.org/10.3945/ajcn.114.092544
Wang, J., You, D., Wang, H., Yang, Y., Zhang, D., Lv, J., Luo, S., Liao, R., & Ma, L. (2020). Association between homocysteine and obesity: A meta‐analysis. In Journal of Evidence-Based Medicine (Vol. 14, Issue 3, pp. 208–217). Wiley. https://doi.org/10.1111/jebm.12412
Zemel, M. B., Richards, J., Mathis, S., Milstead, A., Gebhardt, L., & Silva, E. (2005). Dairy augmentation of total and central fat loss in obese subjects. In International Journal of Obesity (Vol. 29, Issue 4, pp. 391–397). Springer Science and Business Media LLC. https://doi.org/10.1038/sj.ijo.0802880