Summary: Dietary changes associated with industrialization substantially increase the prevalence of chronic diseases, such as obesity, type II diabetes, and cardiovascular disease, which are major contributors to the public health burden. The high prevalence of these chronic diseases is often attributed to an “evolutionary mismatch,” between human physiology and modern nutritional environments. In support of this idea, Western diets enriched with foods that were scarce throughout human evolutionary history (e.g., simple sugars and saturated fats) promote inflammation and disease relative to diets more akin to hunter-gatherer diets, such as a Mediterranean diet; however, the mechanisms linking dietary mismatch to inflammation and chronic disease are poorly understood. We used a macaque model and whole diet manipulations to evaluate one possible mechanism – inflammatory polarization of monocytes – that potentially leads to this evolutionary mismatch. After consuming a Western- or Mediterranean-like diet for 15 months, monocytes from Western diet consumers exhibited a more proinflammatory phenotype, with 40% of their genes differentially expressed (FDR<0.05). Compared to the Mediterranean diet, the Western diet shifted the co-expression of 445 gene pairs, including small RNAs and transcription factors associated with metabolism and adiposity in humans, and dramatically altered animal behavior. For example, Western-fed individuals were more anxious and less socially integrated compared to the Mediterranean-fed subjects. These behavioral changes mediated some of the effects of diet on gene expression, suggesting an interaction between diet, central nervous system activity, and monocyte gene expression. The results of this study provide new insights into evolutionary mismatch at the molecular level and uncover new pathways through which Western diets generate inflammation and disease.
Overall Design: 35 cynomolgus macaques (Macaca fascicularis) were fed experimental diets modeled after human dietary patterns: n = 20 Western diet, n = 15 Mediterranean diet. Experimental diets were formulated to be isocaloric with respect to protein, fat, and carbohydrate macronutrients, and identical in cholesterol content (~ 320mg / 2000 kilocalories (Cals)/day) as described previously by Shively et al. (2019, Obes. Silver Spring Md.). The Western diet was formulated to be similar to that consumed by American women age 40-49 as reported by the US Dept. Agriculture, with protein and fat derived mainly from animal sources. The Western diet was relatively high in saturated fat and sodium, and low in monounsaturated fat and n-3 fatty acids. The Mediterranean diet was formulated to mimic key aspects of the traditional Mediterranean diet, with an n-6:n-3 fatty acid ratio similar to a traditional hunter-gatherer type diet. Protein and fats were derived mainly from plant sources, fish and dairy, and monounsaturated fatty acids were relatively high. Mediterranean diet contained more complex carbohydrates and fiber, and less sodium and refined sugars than Western diet. Key ingredients included English walnut powder and extra-virgin olive oil which were the primary components provided to participants in the PREDIMED study, a landmark dietary intervention study that illustrated the role of the Mediterranean diet on cardiovascular disease prevention (Estruch et al., 2018, N. Engl. J. Med.). A more detailed breakdown of nutritional content can be found in the accompanying publication and in Shively et al. (2019, Obes. Silver Spring Md.). Peripheral blood monocytes were isolated after 15 months on experimental diet and RNA was sequenced using single-end 76-bp reads on an Illumina NextSeq 500 to an average read depth of 34.5 million reads per sample (range 25.9 – 41.6 million reads).
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