Editing Metabolic syndrome (section)

==Pathophysiology==
It is common for there to be a development of [[visceral fat]], after which the [[adipocyte]]s (fat cells) of the visceral fat increase [[blood plasma|plasma]] levels of [[TNF-α]] and alter levels of other substances (e.g., [[adiponectin]], [[resistin]], and [[PAI-1]]). TNF-α has been shown to cause the production of inflammatory [[cytokine]]s and also possibly trigger cell signaling by interaction with a [[TNF receptor superfamily|TNF-α receptor]] that may lead to insulin resistance.<ref>{{Cite journal |vauthors=Hotamisligil GS |date=June 1999 |title=The role of TNFalpha and TNF receptors in obesity and insulin resistance |journal=Journal of Internal Medicine |volume=245 |issue=6 |pages=621–25 |doi=10.1046/j.1365-2796.1999.00490.x |pmid=10395191 |s2cid=58332116 |doi-access=free}}</ref> An experiment with rats fed a diet with 33% [[sucrose]] has been proposed as a model for the development of metabolic syndrome. The sucrose first elevated blood levels of triglycerides, which induced visceral fat and ultimately resulted in insulin resistance. The progression from visceral fat to increased TNF-α to insulin resistance has some parallels to human development of metabolic syndrome. The increase in adipose tissue also increases the number of immune cells, which play a role in inflammation. Chronic inflammation contributes to an increased risk of hypertension, atherosclerosis and diabetes.<ref>Whitney, Ellie and Ralfes, R. Sharon. 2011. ''Understanding Nutrition''. [[Wadsworth Cengage Learning]]: Belmont, CA</ref>

The involvement of the [[endocannabinoid system]] in the development of metabolic syndrome is indisputable.<ref name="ECS - metabolic disorders" /><ref name="ECS - MS" /><ref name="AA and endocannabinoids" /> Endocannabinoid overproduction may induce [[reward system]] dysfunction<ref name="ECS - MS">{{Cite journal |author-link3=Alexandros Makriyannis |vauthors=Vemuri VK, Janero DR, Makriyannis A |date=March 2008 |title=Pharmacotherapeutic targeting of the endocannabinoid signaling system: drugs for obesity and the metabolic syndrome |journal=Physiology & Behavior |volume=93 |issue=4–5 |pages=671–86 |doi=10.1016/j.physbeh.2007.11.012 |pmc=3681125 |pmid=18155257 |quote=The etiology of many appetitive disorders is characterized by a pathogenic component of reward-supported craving, be it for substances of abuse (including alcohol and nicotine) or food. Such maladies affect large numbers of people as prevalent socioeconomic and healthcare burdens. Yet in most instances drugs for their safe and effective pharmacotherapeutic management are lacking despite the attendant medical needs, collateral adverse physical and psychological effects, and enormous global market potential. The endocannabinoid signaling system plays a critical role in motivational homeostasis as a conduit for reward stimuli and a positive modulator of brain reward circuits. Endocannabinoid-system hyperactivity through CB1 receptor transmission is considered contributory to a range of appetitive disorders and, hence, is a major focus of contemporary pharmaceutical research.}}</ref> and cause [[executive dysfunction]]s (e.g., impaired delay discounting), in turn perpetuating unhealthy behaviors.{{medical citation needed|date=April 2016}} The brain is crucial in development of metabolic syndrome, modulating peripheral carbohydrate and lipid metabolism.<ref name="ECS - metabolic disorders">{{Cite book |title=Endocannabinoids |vauthors=Gatta-Cherifi B, Cota D |year=2015 |isbn=978-3-319-20824-4 |series=Handbook of Experimental Pharmacology |volume=231 |pages=367–91 |chapter=Endocannabinoids and Metabolic Disorders |doi=10.1007/978-3-319-20825-1_13 |pmid=26408168 |quote=The endocannabinoid system (ECS) is known to exert regulatory control on essentially every aspect related to the search for, and the intake, metabolism and storage of calories, and consequently it represents a potential pharmacotherapeutic target for obesity, diabetes and eating disorders.&nbsp;... recent research in animals and humans has provided new knowledge on the mechanisms of actions of the ECS in the regulation of eating behavior, energy balance, and metabolism. In this review, we discuss these recent advances and how they may allow targeting the ECS in a more specific and selective manner for the future development of therapies against obesity, metabolic syndrome, and eating disorders.}}</ref><ref name="ECS - MS" />

Metabolic syndrome can be induced by overfeeding with sucrose or fructose, particularly concomitantly with high-fat diet.<ref>{{Cite journal |vauthors=Fukuchi S, Hamaguchi K, Seike M, Himeno K, Sakata T, Yoshimatsu H |date=June 2004 |title=Role of fatty acid composition in the development of metabolic disorders in sucrose-induced obese rats |journal=Experimental Biology and Medicine |volume=229 |issue=6 |pages=486–93 |doi=10.1177/153537020422900606 |pmid=15169967 |s2cid=20966659}}</ref> The resulting oversupply of [[omega-6 fatty acids]], particularly [[arachidonic acid]] (AA), is an important factor in the [[pathogenesis]] of metabolic syndrome.{{medical citation needed|date=April 2016}} Arachidonic acid (with its precursor – [[linoleic acid]]) serves as a substrate to the production of inflammatory mediators known as [[eicosanoids]], whereas the arachidonic acid-containing compound [[diacylglycerol]] (DAG) is a precursor to the endocannabinoid [[2-arachidonoylglycerol]] (2-AG) while [[fatty acid amide hydrolase]] (FAAH) mediates the metabolism of [[anandamide]] into [[arachidonic acid]].<ref name="FAAH">{{Cite journal |vauthors=Di Marzo V, Fontana A, Cadas H, et al. |date=Dec 1994 |title=Formation and inactivation of endogenous cannabinoid anandamide in central neurons |url=http://www.escholarship.org/uc/item/0kh020xm |journal=Nature |type=Submitted manuscript |volume=372 |issue=6507 |pages=686–91 |bibcode=1994Natur.372..686D |doi=10.1038/372686a0 |pmid=7990962 |s2cid=4341716}}</ref><ref name="AA and endocannabinoids">{{Cite journal |vauthors=Turcotte C, Chouinard F, Lefebvre JS, Flamand N |date=June 2015 |title=Regulation of inflammation by cannabinoids, the endocannabinoids 2-arachidonoyl-glycerol and arachidonoyl-ethanolamide, and their metabolites |journal=Journal of Leukocyte Biology |volume=97 |issue=6 |pages=1049–70 |doi=10.1189/jlb.3RU0115-021R |pmid=25877930 |s2cid=206999921}}</ref> Anandamide can also be produced from [[N-Acylphosphatidylethanolamine|''N''-acylphosphatidylethanolamine]] via several pathways.<ref name="AA and endocannabinoids" /> Anandamide and 2-AG can also be hydrolized into arachidonic acid, potentially leading to increased [[eicosanoid]] synthesis.<ref name="AA and endocannabinoids" />