| 词条 | Draft:Inuit Metabolic adapation |
| 释义 |
Genetic and Physiological Metabolic adaptation of The Inuit The Inuit are Indigenous arctic peoples who have a diet uniquely composed of animal products and almost completely devoid of sugars and carbohydrates[1]. The selective pressures of the extreme climate and diet, small founding population, and relative isolation have resulted in many selective gene variants advantageous to a limited and specific diet in the cold stress of an arctic environment. While the Inuit diet would be considered nutritionally inadequate in another population [2], the Inuit are profoundly genetically and physiologically adapted to survive on their traditional diet [3]. The relatively isolated populations have allowed opportunities for genetic research and many of the mutations responsible for these unique survival traits have been identified and described. Some of these described genetic adaptations relate to fat and thermoregulation, metabolism of dietary fatty acids, and glucose metabolism. These specific metabolic advantages are being increasingly challenged by a modern westernized diet, and many could now be considered deleterious and maladaptive in present contexts [4]. Contents:1. Thermoregulation 2. Lipid Metabolism 3. Sugar and carbohydrate Metabolism 4. References 1: ThermoregulationIn addition to exhibiting the anthropometric phenotype that defines physiologic adaptation in accordance with Bergman’s and Allen’s rules for cold climate selection [5], Inuit Greenlanders have unique physiology when it comes to fat distribution and differentiation. Inuit have a gene variation associated with increased production of brown fat [6], an adipose tissue that is more efficient when it comes to generating heat than regular white adipose tissue. This adaption comes from unique alleles within the loci of TBX15/WARS2 region, and is common to Indigenous Greenlanders and some Native Americans, but incredibly rare in Eurasia and completely unidentified in African populations [6]. This haplotype is so divergent that it is believed to have introgressed from a small founding archaic population, and because this gene variant is also shared with the extinct hominin species, Homo sapiens denisova [7], some believe this genetic advantage may have been contributed by ancestral Denisovans. Having a higher body mass index than would be healthier in any other population [8], and having that body mass composed of particularly thermo-efficient fat tissue confers a significant advantage to surviving the cold stress of the extreme arctic climate. 2: Lipid MetabolismIn order to cope with a diet uniquely high in protein, omega 3 polyunsaturated fatty acids and very low in lineolic acids, carbohydrates and plant matter [9], indigenous Greenland Inuit have responded to these pressures with multiple genetic mutations and variations. Many of these variations have a protective effect from the well known risk factors of high tissue levels of fatty acids and high blood plasma lipid levels on cardiovascular disease [10]. In one study of the Nunavik Inuit of northern Canada, multiple genes were identified as having a protective effect. One important finding was that Inuit that were heterozygous for CETP C-4502T (rs183130) or G-971A (rs4783961) genotypes had lower blood triglycerides despite their higher blood and tissue levels of fatty acids. Other identified variations to AGT M235T (rs699) TT genotype, CETP G-971A (rs4783961) AG genotype, T allele carriers of CETP C-4502T (rs183130), and T allele carriers of CETP Ile405Val (rs5882) had an effect of lowering total cholesterol as well as lipoprotein cholesterol levels [10]. While the exact mechanisms of how newly discovered mutations may benefit the healthy metabolism of such a seemingly unbalanced diet, it is known that a group of genes, CPT1A, CPT1B, CPT1C, CPT2, CRAT and CROT, are integral to the oxidation and metabolism of fatty acids [11] and regulate how they are used and converted by the body for energy and brain function. In an examination of these genes among the Nunavik Inuit, ten missense mutation variants were identified, including a very specific variant found only within this population, named CPT1A p.P479L (rs80356779) [11]. When compared to European and Asian genetic profiles, Inuit have a significantly increased burden of mutation in three of these genes, CPT1A, CPT2 and CRAT, and it can be suggested that these mutations have resulted from pressure to adapt to the extreme climate and diet of the Inuit when compared with these other populations [11]. 3: Sugar and Carbohydrate MetabolismThe traditional Inuit diet contains only negligible amounts of carbohydrates and glucose [1], because the body continually needs glucose [12] for many physiological processes this allows unique research questions to be asked into how the Inuit have adapted to produce it and utilize it metabolically while lacking the conventional dietary sources. While glucose is easily converted into fatty acids in most humans, it appears the Inuit have adapted to the reverse of this and have some capacity to convert fatty acids into glucose [12]. This gluconeogenesis from fatty acids was previously thought to be impossible before the discovery of a glyoxylate shunt [Fig. 1] that is not generally present in mammals. The discovery of this unknown metabolic route has particular relevance in understanding the unique metabolism of Inuit and other indigenous Arctic peoples and has reaching importance to human biology and the ability for humans to survive in times of carbohydrate scarcity. While these populations have an increased ability to produce glucose from fatty acids [12], other mutations have been identified within them related to glucose and insulin. While their function within a traditional diet is unknown, they are now deleterious and maladapted to an increasingly modern diet. One identified mutation is a nonsense p.Arg684Ter variant in the gene TBC1D4 [13], the homozygous carriers of this variant have impaired glucose tolerance, higher plasma glucose levels, and significantly higher fasting glucose levels. This type of glucose intolerance also causes issues with the glucose transporters in muscles, and is associated with a dramatically increased risk of type 2 diabetes [13]. Another deleterious mutation common to Inuit is located in SI c.273_274delAG, and is responsible for congenital sucrase–isomaltase deficiency[14]. This gene variant causes individuals to lack an enzyme for the digestion of disaccharides and oligosaccharides, including sucrase and isomaltase. This disease is a rare autosomal recessive form of carbohydrate malabsorption and causes severe fermentative and chronic diarrhea [14]. It is particularly deleterious to children, and contributes to failure to thrive and wasting in very young children. It is relatively rare, being found only in .02% of European admixtures, compared to 10% within the Inuit [14]. Symptoms begin when sucrase containing foods are consumed, sucrase containing foods like fruit that do not exist within a traditional Inuit diet [1] and that the Inuit are now highly maladapted to metabolize them. References1.Bang HO, Dyerberg J, Hjørne N. The Composition of Food Consumed by Greenland Eskimos. Acta Medica Scandinavica. 2009;200(1-6):69–73. 2. Hopping BN, Mead E, Erber E, Sheehy C, Roache C, Sharma S. Dietary adequacy of Inuit in the Canadian Arctic. Journal of Human Nutrition and Dietetics. 2010Jul;23:27–34. 3.Gloyn A, Thomsen SK. Faculty of 1000 evaluation for Greenlandic Inuit show genetic signatures of diet and climate adaptation. F1000 - Post-publication peer review of the biomedical literature. 2015May 4.Bogan J. Faculty of 1000 evaluation for A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes. F1000 - Post-publication peer review of the biomedical literature. 2014; 5.Christopher B.Ruff. Climate and body shape in hominid evolution. Journal of Human Evolution 19991; 21(2): . 6.Fumagalli M Greenlandic inuit show genetic signatures of diet and climate adaptation: Science: 2015; 12(1343-1347): 10-12. 7. Racimo F, Gokhman D, Fumagalli M, Ko A, Hansen T, Moltke I, et al. Archaic adaptive introgression in TBX15/WARS2. Molecular Biology and Evolution. 2016; 8.Andersen S, Rex KF, Noahsen P, Sørensen HCF, Mulvad G, Laurberg P. Raised BMI cut-off for overweight in Greenland Inuit – a review. International Journal of Circumpolar Health. 2013;72(1):21086. 9.Bang HO, Dyerberg J, Hjørne N. The Composition of Food Consumed by Greenland Eskimos. Acta Medica Scandinavica. 2009;200(1-6):69–73. 10.Rudkowska I, Ouellette C, Dewailly E, Hegele RA, Boiteau V, Dubé-Linteau A, et al. Omega-3 fatty acids, polymorphisms and lipid related cardiovascular disease risk factors in the Inuit population. Nutrition & Metabolism. 2013;10(1):26 11. Zhou S, Xiong L, Xie P, Ambalavanan A, Bourassa CV, Dionne-Laporte A, et al. Increased Missense Mutation Burden of Fatty Acid Metabolism Related Genes in Nunavik Inuit Population. Plos One. 2015;10(5). 12. Kaleta C, de Figueiredo LF, Schuster S. Against the stream: relevance of gluconeogenesis from fatty acids for natives of the arctic regions. Int J Circumpolar Health. 2012;71(0):1-2. Published 2012 May 3. doi:10.3402/ijch.v71i0.18436 13. Bogan J. Faculty of 1000 evaluation for A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes. F1000 - Post-publication peer review of the biomedical literature. 2014; 14. Marcadier JL, Boland M, Scott CR, Issa K, Wu Z, Mcintyre AD, et al. MG-107 Congenital sucrase-isomaltase deficiency: Identification of the common inuit founder mutation. Journal of Medical Genetics. 2015;52(Suppl 1). Genetic and Physiological Metabolic adaptation of The Inuit |
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