The Power of Nutrition (Part 6): How Does Nutrition Work?

Molecular Mechanisms of Nutrition and Disease

Diet constitutes one of the most important modifiable risk factors for all kinds of diseases. How exactly can food influence our health? With this article, PAN wants to illuminate some of the basic mechanisms of how nutrition acts on our metabolism.

We Are Made from Food

It may sound clichéd, but it’s true: food is life. Food and its components are the basic substrate for our structure and our metabolism. Without food, there is no development, no growth, no warmth, no movement, no reproduction, and no cognition.

Compared to other risk factors, such as smoking, physical inactivity or UV radiation, diet is more complex. We consume a lot of different foods, and each food item is made of thousands of substances with potential effects on our body. In addition, these substances usually don’t work individually, but in compounds, each with their own specific effects.

Food components can be broken down into macronutrients on the one hand and micronutrients on the other hand.

Macronutrients and Their Functions

Macronutrients such as proteins, carbohydrates, and fats have in common that they provide energy for the organism. Micronutrients, such as minerals or vitamins, take more of a supportive role in metabolism, meaning that they work as cofactors or coenzymes¹⁾Berg JM, Stryer L, Tymoczko JL, Gatto GJ. Biochemistry. 8th ed. New York: WH Freeman; 2015..

Carbohydrates are the primary energy source for our body. They are also needed for DNA and RNA synthesis, and, in synergy with proteins and fats, they form glycoproteins and glycolipids that work in cell communication and signaling²⁾Berg JM, Stryer L, Tymoczko JL, Gatto GJ. Biochemistry. 8th ed. New York: WH Freeman; 2015..

Proteins serve both as an energy source and a substrate for our bodily structure. In the form of enzymes, they also work as molecular “instruments” of our metabolism, which makes them essential for every biochemical reaction to work. Forming antibodies, they are an essential element of our immune system. As structural proteins, they constitute the building of our tissue and our whole morphology. Myosin and actin, two important proteins, are needed for our muscles and hence bodily movements. Proteins are also essential for the transportation of molecules such as oxygen or iron, and they constitute clotting factors needed for hemostasis³⁾Berg JM, Stryer L, Tymoczko JL, Gatto GJ. Biochemistry. 8th ed. New York: WH Freeman; 2015..

Fats, or fatty acids, provide an energy storage system for our body. Additionally, they are essential for the absorption of fat-soluble vitamins such as vitamin E, D, K and A. They are constituents of the cell membrane and myelin sheaths and work as a protective cushion for our organs⁴⁾Berg JM, Stryer L, Tymoczko JL, Gatto GJ. Biochemistry. 8th ed. New York: WH Freeman; 2015..

Micronutrients and Their Role for Metabolism

Micronutrients, such as vitamins, minerals or phytochemicals, are substances that need to be ingested but don’t provide energy. They are essential for anabolic and catabolic reactions of our metabolism. As there are thousands of micronutrients, only a few can be mentioned here, representing examples for the enormous variety of functions.

• Iodine, for instance, is a chemical element required for the synthesis of the growth-regulating thyroid hormones thyroxine and triiodothyronine⁵⁾Berg JM, Stryer L, Tymoczko JL, Gatto GJ. Biochemistry. 8th ed. New York: WH Freeman; 2015.
• Iron is an essential trace element needed for hematopoiesis. It constitutes the central atom of the hem cofactor in hemoglobin and myoglobin and is hence required for oxygen transport. It’s also an important component of many enzymes and part of the electron transport chain in mitochondria required for ATP production⁶⁾Berg JM, Stryer L, Tymoczko JL, Gatto GJ. Biochemistry. 8th ed. New York: WH Freeman; 2015.
• Vitamin K is essential for the activation of clotting factors, and it’s involved in bone metabolism⁷⁾Berg JM, Stryer L, Tymoczko JL, Gatto GJ. Biochemistry. 8th ed. New York: WH Freeman; 2015.⁸⁾Palermo A, Tuccinardi D, D’Onofrio L, et al. Vitamin K and osteoporosis: Myth or reality? Metab Clin Exp. 2017;70:57-71. doi:1016/j.metabol.2017.01.032
• Omega-3-fatty acids are required for functioning cell membranes and for the synthesis of anti-inflammatory prostaglandins⁹⁾Berg JM, Stryer L, Tymoczko JL, Gatto GJ. Biochemistry. 8th ed. New York: WH Freeman; 2015.¹⁰⁾Endo J, Arita M. Cardioprotective mechanism of omega-3 polyunsaturated fatty acids. J Cardiol. 2016;67(1):22-27. doi:1016/j.jjcc.2015.08.002
• L-arginine is a semi essential amino acid that is a precursor for the synthesis of nitric oxide, an important second messenger involved in vasodilation and blood pressure regulation¹¹⁾Berg JM, Stryer L, Tymoczko JL, Gatto GJ. Biochemistry. 8th ed. New York: WH Freeman; 2015.¹²⁾Joshi MS, Ferguson TB, Johnson FK, Johnson RA, Parthasarathy S, Lancaster JR. Receptor-mediated activation of nitric oxide synthesis by arginine in endothelial cells. Proc Natl Acad Sci USA. 2007;104(24):9982-9987. doi:1073/pnas.0506824104

What Too Much or Too Little Does to Our Body

As one can see from the great number of functions fulfilled by macro- and micronutrients, both deficiency and excess can lead to metabolic disturbances.

For example, starvation, i.e. the deficiency of both macro- and micronutrients, causes cachexia, and, eventually, death. In children, malnutrition can lead to stunted growth.

Speaking of a moderate form, malnutrition can cause fatigue, apathy and depression, muscle atrophy, delayed wound healing, an elevated risk for infections, and a reduced cardiac output.

Common conditions associated with micronutrient deficiencies are, for example, anemia (by lack of i.a. iron, vitamin B12, folic acid), osteoporosis (i.a. calcium, vitamin D), goiter or cretinism (iodine), subacute degeneration of spinal cord (vitamin B12, folic acid), spina bifida (folic acid), muscle cramps (i.a. magnesium), and immune disorders (vitamins A, D, E; zinc, iron, selenium) ¹³⁾Calder PC. Feeding the immune system. Proc Nutr Soc. 2013;72(3):299-309. doi:10.1017/S0029665113001286. A lack of phytochemicals such as polyphenols also has consequences on health, which will be discussed later.

On the other hand, overnutrition eventually causes obesity, resulting in an increased risk for cardiovascular disease, cancer, and other conditions. An excess ingestion of single specific substances, such as trans fatty acids¹⁴⁾Brouwer IA, Wanders AJ, Katan MB. Trans fatty acids and cardiovascular health: research completed? Eur J Clin Nutr. 2013;67(5):541-547. doi:10.1038/ejcn.2013.43, arsenic¹⁵⁾Kuo C-C, Howard BV, Umans JG, et al. Arsenic Exposure, Arsenic Metabolism, and Incident Diabetes in the Strong Heart Study. Diabetes Care. 2015;38(4):620-627. doi:10.2337/dc14-1641, cadmium¹⁶⁾Huang Y, He C, Shen C, et al. Toxicity of cadmium and its health risks from leafy vegetable consumption. Food Funct. 2017;8(4):1373-1401. doi:10.1039/c6fo01580h, and pyrrolizidine alkaloids¹⁷⁾Habs M, Binder K, Krauss S, et al. A Balanced Risk-Benefit Analysis to Determine Human Risks Associated with Pyrrolizidine Alkaloids (PA)-The Case of Tea and Herbal Infusions. Nutrients. 2017;9(7). doi:10.3390/nu9070717, for example, also interferes with metabolic processes and leads to health problems.

The subsequent sections will go more deeply into specific disease mechanisms certain foods or diets can have an impact on, i.e. signaling and cell communication via hormones, inflammation, and oxidative stress. Two other important mechanisms, such as epigenetics and the human microbiome, affecting the immune system in particular, have already been discussed in detail in two separate blog articles.

How Does Overconsumption Cause Metabolic and Hormonal Disturbances?

An excess of food ultimately leads to obesity¹⁸⁾Spiegelman BM, Flier JS. Obesity and the regulation of energy balance. Cell. 2001;104(4):531-543.. Obesity, on a histological level, describes the presence of an increased amount of white adipose tissue. In an obese person, adipocytes release a high amount of fatty acids because of increased lipolysis due to an upregulated sympathetic nervous system¹⁹⁾Redinger RN. The Pathophysiology of Obesity and Its Clinical Manifestations. Gastroenterol Hepatol (N Y). 2007;3(11):856-863.. These free fatty acids cause oxidative stress to different tissues, leading to insulin-receptor dysfunction, insulin resistance, and hyperglycemia. Free fatty acids also decrease the amount of utilized muscle-glucose, which additionally leads to hyperglycemia²⁰⁾Pan DA, Lillioja S, Kriketos AD, et al. Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes. 1997;46(6):983-988..

Insulin is supposed to be a proatherogenic hormone, promoting the development of cardiovascular disease²¹⁾Després JP, Lamarche B, Mauriège P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med. 1996;334(15):952-957. doi:10.1056/NEJM199604113341504²²⁾Madonna R, Pandolfi A, Massaro M, Consoli A, De Caterina R. Insulin enhances vascular cell adhesion molecule-1 expression in human cultured endothelial cells through a pro-atherogenic pathway mediated by p38 mitogen-activated protein-kinase. Diabetologia. 2004;47(3):532-536. doi:10.1007/s00125-004-1330-x.

How Does Diet Cause Cancer?

Adipose tissue also releases adipokines that promote cancer via the stimulation of insulin-like growth factor-1 (IGF-1) and other growth hormones, which enhance cellular proliferation or dedifferentiation due to mitogenic and antiapoptotic signaling cascades²³⁾Orrù S, Nigro E, Mandola A, et al. A Functional Interplay between IGF-1 and Adiponectin. Int J Mol Sci. 2017;18(10). doi:10.3390/ijms18102145²⁴⁾ Anisimov VN, Bartke A. The key role of growth hormone-insulin-IGF-1 signaling in aging and cancer. Crit Rev Oncol Hematol. 2013;87(3):201-223. doi:10.1016/j.critrevonc.2013.01.005. IGF-1 also enhances angiogenesis, which promotes general cancer growth²⁵⁾Renehan AG, Frystyk J, Flyvbjerg A. Obesity and cancer risk: the role of the insulin-IGF axis. Trends Endocrinol Metab. 2006;17(8):328-336. doi:10.1016/j.tem.2006.08.006. Leptin itself, one of the well-researched adipokines, is known to have mitogenic, anti-apoptotic, and pro-inflammatory properties, all being involved in carcinogenesis²⁶⁾Lee CH, Woo YC, Wang Y, Yeung CY, Xu A, Lam KSL. Obesity, adipokines and cancer: an update. Clin Endocrinol (Oxf). 2015;83(2):147-156. doi:10.1111/cen.12667.

It’s not only white adipose tissue that promotes cancer; it’s also dietary (pro-)carcinogens, such as mycotoxins, for example, that have carcinogenic properties. Aflatoxin from mold-contaminated food forms adducts with DNA, which induces the development of liver cancer²⁷⁾Kew MC. Aflatoxins as a cause of hepatocellular carcinoma. J Gastrointestin Liver Dis. 2013;22(3):305-310.. Benzo[a]pyrene can be found predominantly in grilled meats²⁸⁾Lee BM, Shim GA. Dietary exposure estimation of benzo[a]pyrene and cancer risk assessment. J Toxicol Environ Health Part A. 2007;70(15-16):1391-1394. doi:10.1080/15287390701434182. Its metabolites also interfere with DNA which promotes mutations and hereby cancer²⁹⁾Volk DE, Thiviyanathan V, Rice JS, et al. Solution structure of a cis-opened (10R)-N6-deoxyadenosine adduct of (9S,10R)-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene in a DNA duplex. Biochemistry. 2003;42(6):1410-1420. doi:10.1021/bi026745u. A disbalance between pro- and antioxidative components in our food might also play a role in cancer formation ³⁰⁾Sharma A, Kaur M, Katnoria JK, Nagpal AK. Polyphenols in Food: Cancer Prevention and Apoptosis Induction. Curr Med Chem. 2018;25(36):4740-4757. doi:10.2174/0929867324666171006144208, which will be clarified in the paragraph below.

What Are the Mechanisms by Which Food Causes Inflammation?

Oxidants and antioxidants are also involved in inflammation, another basic disease mechanism nutrition is acting on. Inflammation is a cellular response to an injury characterized by increased blood flow, leukocyte infiltration, and local production of mediators with the purpose of tissue repair³¹⁾Calder PC, Ahluwalia N, Albers R, et al. A consideration of biomarkers to be used for evaluation of inflammation in human nutritional studies. Br J Nutr. 2013;109 Suppl 1:S1-34. doi:10.1017/S0007114512005119. It is the underlying disease mechanisms of conditions. such as the metabolic syndrome, non-alcoholic-fatty-liver disease, diabetes mellitus, and cardiovascular diseases³²⁾Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444(7121):860-867. doi:10.1038/nature05485.

Again, it’s overnutrition, i.e. obesity, that is one of the most important causes of a pro-inflammatory bodily state. White adipose tissue, more precisely, visceral fat depots release adipokines that stimulate cytokines, such as TNF-alpha, IL-1 and IL-6, that can cause systemic inflammation³³⁾Lafontan M. Fat cells: afferent and efferent messages define new approaches to treat obesity. Annu Rev Pharmacol Toxicol. 2005;45:119-146. doi:10.1146/annurev.pharmtox.45.120403.095843³⁴⁾Calabro P, Yeh ET. Obesity, inflammation, and vascular disease: the role of the adipose tissue as an endocrine organ. Subcell Biochem. 2007;42:63-91.. This is yet another mechanism by which adipose tissue causes pancreatic beta-cell-dysfunction and hereby hyperglycemia and eventually diabetes mellitus³⁵⁾Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89(6):2548-2556. doi:10.1210/jc.2004-0395.

In contrast, a negative energy balance, i.e. caloric restriction, reduces inflammation³⁶⁾Fontana L, Meyer TE, Klein S, Holloszy JO. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci USA. 2004;101(17):6659-6663. doi:10.1073/pnas.0308291101.

Inflammation is also involved in the development of atherosclerosis by inducing endothelial dysfunction and vascular injury. In addition to pro-inflammatory adipokines and also an adipocyte-derived renin-angiotensin-aldosterone-system³⁷⁾Engeli S, Schling P, Gorzelniak K, et al. The adipose-tissue renin-angiotensin-aldosterone system: role in the metabolic syndrome? Int J Biochem Cell Biol. 2003;35(6):807-825., inflammation is promoted by an increased amount of oxidative stress.

Oxidative stress is a metabolic state characterized by a disbalance between the presence of reactive oxygen species (ROS) and antioxidant molecules able to counteract the emerging free radicals. As free radicals have the potential to damage all components within a cell, including proteins, lipids and also DNA, oxidative stress, i.e. an excessive amount of ROS is involved in most diseases, from cancer³⁸⁾Halliwell B. Oxidative stress and cancer: have we moved forward? Biochemical Journal. 2007;401(1):1-11. doi:10.1042/BJ20061131³⁹⁾Carini F, Mazzola M, Rappa F, et al. Colorectal Carcinogenesis: Role of Oxidative Stress and Antioxidants. Anticancer Res. 2017;37(9):4759-4766. doi:10.21873/anticanres.11882 to cardiovascular disease⁴⁰⁾Siti HN, Kamisah Y, Kamsiah J. The role of oxidative stress, antioxidants and vascular inflammation in cardiovascular disease (a review). Vascul Pharmacol. 2015;71:40-56. doi:10.1016/j.vph.2015.03.005 to neurogenerative⁴¹⁾Niedzielska E, Smaga I, Gawlik M, et al. Oxidative Stress in Neurodegenerative Diseases. Mol Neurobiol. 2016;53(6):4094-4125. doi:10.1007/s12035-015-9337-5 and psychiatric disorders⁴²⁾Jiménez-Fernández S, Gurpegui M, Díaz-Atienza F, Pérez-Costillas L, Gerstenberg M, Correll CU. Oxidative stress and antioxidant parameters in patients with major depressive disorder compared to healthy controls before and after antidepressant treatment: results from a meta-analysis. J Clin Psychiatry. 2015;76(12):1658-1667. doi:10.4088/JCP.14r09179. ROS-related oxidation of DNA is one of the main causes of mutations which promotes carcinogenesis⁴³⁾Kawanishi S, Ohnishi S, Ma N, Hiraku Y, Murata M. Crosstalk between DNA Damage and Inflammation in the Multiple Steps of Carcinogenesis. Int J Mol Sci. 2017;18(8). doi:10.3390/ijms18081808.

Prooxidant molecules are a byproduct of energy metabolism, caused by cellular respiration, but there are also exogenous sources, such as smoking, heavy metals or pesticides⁴⁴⁾Phaniendra A, Jestadi DB, Periyasamy L. Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases. Indian J Clin Biochem. 2015;30(1):11-26. doi:10.1007/s12291-014-0446-0. Diet can influence the production of both pro- and antioxidant molecules. For example, increased consumption of saturated fatty acids increases oxidative stress, whereas monounsaturated fatty acids take on more of an antioxidant role⁴⁵⁾Vetrani C, Costabile G, Di Marino L, Rivellese AA. Nutrition and oxidative stress: a systematic review of human studies. International Journal of Food Sciences and Nutrition. 2013;64(3):312-326. doi:10.3109/09637486.2012.738651.

Dietary polyphenols found in fruits, vegetables, dark chocolate, tea, coffee or wine, act as antioxidants or increase antioxidant gene expression and in this way antagonize inflammation⁴⁶⁾Scalbert A, Manach C, Morand C, Rémésy C, Jiménez L. Dietary polyphenols and the prevention of diseases. Crit Rev Food Sci Nutr. 2005;45(4):287-306. doi:10.1080/1040869059096⁴⁷⁾Chun OK, Chung S-J, Claycombe KJ, Song WO. Serum C-reactive protein concentrations are inversely associated with dietary flavonoid intake in U.S. adults. J Nutr. 2008;138(4):753-760. doi:10.1093/jn/138.4.753⁴⁸⁾ Landberg R, Sun Q, Rimm EB, et al. Selected dietary flavonoids are associated with markers of inflammation and endothelial dysfunction in U.S. women. J Nutr. 2011;141(4):618-625. doi:10.3945/jn.110.133843.

To summarize, food is the matter we are built from, and its components power our metabolism. Food affects our DNA, all of our organ systems, our well-being. This article only gives a hint of the underlying disease mechanisms and their interactions nutrition has an influence on. They will be elucidated further in the upcoming articles on nutrition and disease.

This article is part of the series “The Power of Nutrition”.