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Obesity and its comorbidities
https://www.ncbi.nlm.nih.gov/books/NBK278973/

General
Disbalance between organ/tissue activation and NO-dependent circulatory adjustement: the multi-entrance, self-perpetuating, vicious circle underlying obesity-related metabolic disease

Endothelial NO deficit, vasodilatation failure, hypoxia, cell death, local inflammation, systemic proinflammatory state, derived microcirculation failure: a multi-entrance, self-perpetuating vicious circle underlying metabolic syndrome and T2D.

TWO MORE ELEMENTS:

-free radicals

-hypertension

Functional reserve.
All organs and tissues of the body operate at different intensities at different moments, higher intensities generally involving increased energy expenditure per time unit, this is ensured in good part by corresponding  increases in blood flow generally mediated by a local surge of nitric oxide (NO) production at the endothelial level, which in turn ensures local compensatory vasodilation, capillary recruitment and increased blood flow to provide more oxygen and metabolic fuels to the tissue performing intense work. Failure of such NO-mediated circulatory compensation in response to increased work load can lead to a deleterious sequence of events: relative hypoxia at the local level, metabolic stress, cell death, macrophage activation, and inflammation if the circulatory failure occuring under such circumstances becomes frequent and/or chronic.

The belief that NO surge is the chemical signal dominating microcirculatory adjustment to short-term organ/tissue activation offers an interesting lead towards a unifying view of the pathophysiological dinamics underlying metabolic-syndrome associated disease.

Key elements of such a unifying view are given below:

Is eNOS expression insulin dependent? Is insulin action NO-dependent?
The expression of eNOS appears to be closely related to insulin action on endothelial cells. Furthermore, low epression of eNOS in arterial endothelium has been reported in T2D.

Thus, the availability of NO at the endothelial level appears to be compromised in T2D, either as a result of inadequate synthesis by insufficient expression of eNOS and/or by increased chemical removal of NO by an excess of free radicals in the local tissue mileau. Microirrigation failures chronically occuring in T2D may in turn be responsible for increased cell death, local inflammation and export of proinflammatory mediators to the general circulation, thereby contributing to further resistance to the trophic action of insulin required to sustain endocyte biochemical make-up and normal NO releleasing functions.

Can insulin-resistance/NO failure cause inflammation?
If insulin signal  is essential to the normal expression of eNOS (probably via AMP-activated protein kinase, AMPK), once minimally installed, insulin resistance will likely lead to insufficient NO levels in organs or tissues, especially when tissue workload intensifies and irrigation needs increase. Persistent microcirculatory failure due to insufficient NO will then lead to tissue inflammation and proinflammatory export, as explained above.

From local inflammation to systemic proinflammatory state.
The occurence of inflammatory phenomena in tissues from T2 diabetic subjects has been documented for nerve, kidney, liver, muscle, heart, adipose tissue, endocrine pancreas and gastric wall, among other locations. The export of proinflammatory species into the circulation will thus favor further vascular insulin resistance and microcirculation failure in organs distant to the initiating damage.

Suggestively enough, histological signs of chronic inflammation have been described in gastric biopsies from insulin-resistant patients undergoing bariatric surgery, Furthermore, clinical signs of gastric wall inflammation, such as grastroparesis, are frequent in diabetic patients.

Foregut (subclinical?) inflammation as a triggering factor in T2D.
Given the above panorama, and as a result of systemic inflammation propensity, whatever the location of initial inflammatory phenomena in T2D, chances are that organ overwork at the foregut level may contribute to its own inflammation, and  a resulting increase of proinflammatory circulating signals that will further interfere with insulin action elesewhere.

Mesenteric lymphatic dysfunction
Cao, Enyuan; Watt, Matthew J.; Nowell, Cameron J.; Quach, Tim; Simpson, Jamie S.; De Melo Ferreira, Vilena; Agarwal, Sonya; Chu, Hannah; Srivastava, Anubhav; Anderson, Dovile; Gracia, Gracia (2021-09-01). "Mesenteric lymphatic dysfunction promotes insulin resistance and represents a potential treatment target in obesity". Nature Metabolism. 3 (9): 1175–1188. doi:10.1038/s42255-021-00457-w. ISSN 2522-5812. PMID 34545251

Does polyfagia lead to proinflammatory foregut overfilling?
The progression of insufficiently checked T2D will eventually lead to the occurence of glucosuria, which -if sufficiently sustained- will give origin to hyperphagia. Hyperphagia in turn is likely to lead to overfilling of the foregut at meal time. The resulting overstretch of foregut walls caused by hyperphagia may significantly contribute to gastric inflammation with its systemic proinflammatory consequences, and its inevitable effects to the sustainment of resistance to the hormone at every inslin target tissue.

Does bariatric surgery stop foregut inflammation caused by overfilling?
Bariatric surgery in any of its modalities leads to the suspension of gastric filling (or overfilling) with food. Once performed, bariatric surgery is known to lead to a rapid improvement of glycemic control in T2 diabetic patients, the effect becoming dramatically evident as early as 2 weeks after surgery. It thus seems likely that termination of gastric overfilling by BS will alleviate its prior inflammation presumably occuring prior to surgery, such diabetogenic inflammation conceivably subsiding within the two-week period when the rapid improvement of glycemic control and insulin sensitivity has been reported to occur after BS. Histological signs of inflammation have

Could bariatric surgery lower systemic inflammatory state, and thereby improve pancreatic insulin release?
In the context described, it would be hardly surprising if BS did not cause a rapid improvement of glycemia and insulinemia, especially if -as likely- concurrent beta cell inflammation secondarily also subsides, and if irrigation improves everywhere as a result of an improvement in microcirculatory recruitment in response to routine episodes of high demand by target and even "not target" tissues and organs.

Is BS-alleviation of systemic inflammation reflected as an improvement in circulating inflammatory markers?
For similar reasons BS will also lead to a rapid fall of abnormally high circulating levels of heat-shock proteins known to occur in T2D. A corresponding alleviation of adipose tissue inflammation by BS would explain reports of the normalization of adiponectin levels in fat cused by this type of surgery. 29024428* 34441954 34685777(DNA damage) 30840227 32522349* (*=CRP)

UK BS statistics
McGlone, Emma Rose; Carey, Iain; Veličković, Vladica; Chana, Prem; Mahawar, Kamal; Batterham, Rachel L.; Hopkins, James; Walton, Peter; Kinsman, Robin; Byrne, James; Somers, Shaw (2020-12). "Bariatric surgery for patients with type 2 diabetes mellitus requiring insulin: Clinical outcome and cost-effectiveness analyses". PLoS medicine. 17 (12): e1003228. doi:10.1371/journal.pmed.1003228. ISSN 1549-1676. PMC 7721482. PMID 33285553

Does hyperlactatemia reflect irrigation failure in T2D?
Although not generally reported, hyperlactatemia may accompany obesity and T2D. Fasting lactate has been reported high in a proportion of obese T2D patients undergoing BS, with an improvement in such levels occuring only days weeks after surgery. Although such hyperlactinemia may reflect irrrigation failure, it has been interpreted to unveil the occurence of mitochondrial difunction in T2D. The question remains as to whether such mitochondrial failure is secondary to tissue damage due to circulatory failure; also whether hyperlactatemia in in this case may have been a side effect of metformin treatment.

Is T2D just the modality of metabolic disease accompanied by hyperglycemia
A number of biochemical abnormalities commonly occuring in various diseases are known to cause insulin resistance even in the absence of diabetes, among them hyperlipidemia 28011403

Endothelial disfunction
It thus seems that NO-dependent endothelial disfunction with subsequent irrigation-adjustment failure, often accompanied by a generalized inflammatory state may be basic underlying lesions occurring in clinical T2D and metabolic syndrome. Although not an absolute proof of the molecular cause of human T2D, an NO-related, endothelial lesional background (together with obesity, insulin resistance, hypertension, nephroáthy, retinopathy, hyperlipidemia, hyperglycemia and impaired functional vasodilation) has been widely confirmed to occur in the Zucker rat, one of the most thoroughly validated animal models of human metabolic-syndrome diseases.

Tissue renewal
All tissues undergo renewal processes whereby obsolete cells will die to be replaced by freshly generated ones in a normally harmonious way, whereby decaying units will be degraded through regular lytic phenomena operating at a "tonic" pace devoid of overt inflammation signs. This non-inflammatory state will only be kept when tissular work load, irrigation and circulation operate smoothly in a geared fashion. The occurence of persistent discordance between tissue renewal phenomena will likely lead to dysynchronization, with likely overstay and overpresence of macrophages and local inflammation. This tissular "aneutrophism" may be a main triggering factor for the subsequent installation of the overt semiological signs of MS and T2D.

Gastric bypass, rapid improvement
Brachial artery vasoreactivity rapidly improved after GBP: Lind, L.; Zethelius, B.; Sundbom, M.; Edén Engström, B.; Karlsson, F. A. (2009-12). "Vasoreactivity is rapidly improved in obese subjects after gastric bypass surgery". International Journal of Obesity (2005). 33 (12): 1390–1395. doi:10.1038/ijo.2009.188. ISSN 1476-5497. PMID 19752874

Arterial stiffnes and oxidative stress in obesity:

 * Czippelova, Barbora; Turianikova, Zuzana; Krohova, Jana; Wiszt, Radovan; Lazarova, Zuzana; Pozorciakova, Katarina; Ciljakova, Miriam; Javorka, Michal (2019-11-01). "Arterial Stiffness and Endothelial Function in Young Obese Patients - Vascular Resistance Matters". Journal of Atherosclerosis and Thrombosis. 26 (11): 1015–1025. doi:10.5551/jat.47530. ISSN 1880-3873. PMC 6845697. PMID 30930343
 * Martínez-Martínez, Ernesto; Souza-Neto, Francisco V.; Jiménez-González, Sara; Cachofeiro, Victoria (2021-03-08). "Oxidative Stress and Vascular Damage in the Context of Obesity: The Hidden Guest". Antioxidants (Basel, Switzerland). 10 (3): 406. doi:10.3390/antiox10030406. ISSN 2076-3921. PMC 7999611. PMID 33800427

Obesity & endothelial disfunction
30949772,30618843,30165404,29036612,28607631,28585207,28482008,28336559,27920727,27130266,27000854,26265791,25001649,24767726,24744283,24138787,22961567,21686173


 * Jonk, Amy M.; Houben, Alfons J.; Schaper, Nicolaas C.; de Leeuw, Peter W.; Serné, Erik H.; Smulders, Yvo M.; Stehouwer, Coen D. (2011-11-01). "Obesity is associated with impaired endothelial function in the  postprandial state ". Microvascular Research. 82 (3): 423–429. doi:10.1016/j.mvr.2011.08.006. ISSN 1095-9319. PMID 21875604


 * Al-Tahami, Belqes Abdullah; Bee, Yvonne-Tee Get; Ismail, Abdul Aziz Al-Safi; Rasool, Aida Hanum Ghulam (2011-01-01). "Impaired microvascular endothelial function in relatively young obese humans is associated with altered metabolic and inflammatory markers". Clinical Hemorheology and Microcirculation. 47 (2): 87–97. doi:10.3233/CH-2010-1370. ISSN 1386-0291
 * Sorop, Oana; Olver, T. Dylan; van de Wouw, Jens; Heinonen, Ilkka; van Duin, Richard W.; Duncker, Dirk J.; Merkus, Daphne (2017-07-01). "The microcirculation: a key player in obesity-associated cardiovascular disease". Cardiovascular Research. 113 (9): 1035–1045. doi:10.1093/cvr/cvx093. ISSN 0008-6363

Peristalsis - vagus
Fasth, S.; Martinson, J. (1973-11-01). "On the possible role of bradykinin in functional hyperemia of cat's stomach". Acta Physiologica Scandinavica. 89 (3): 334–341. doi:10.1111/j.1748-1716.1973.tb05528.x. ISSN 0001-6772. PMID 4767235

Martinson, J. (1965-12-01). "The effect of graded vagal stimulation on gastric motility, secretion and blood flow in the cat". Acta Physiologica Scandinavica. 65 (4): 300–309. doi:10.1111/j.1748-1716.1965.tb04277.x. ISSN 0001-6772. PMID 5880497

Fasth, S.; Hultén, L.; Jahnberg, T.; Martinson, J. (1975-01-01). "Comparative studies on the effects of bradykinin and vagal stimulation on motility in the stomach and colon". Acta Physiologica Scandinavica. 93 (1): 77–84. doi:10.1111/j.1748-1716.1975.tb05792.x. ISSN 0001-6772. PMID 1155133

Vagus - nitric
Tanaka, T.; Guth, P.; Taché, Y. (1993-02). "Role of nitric oxide in gastric hyperemia induced by central vagal stimulation". The American Journal of Physiology. 264 (2 Pt 1): G280–284. doi:10.1152/ajpgi.1993.264.2.G280. ISSN 0002-9513. PMID 8447409

Király, A.; Sütö, G.; Guth, P. H.; Taché, Y. (1998-01). "Peripheral mediators involved in gastric hyperemia to vagal activation by central TRH analog in rats". The American Journal of Physiology. 274 (1): G170–177. doi:10.1152/ajpgi.1998.274.1.G170. ISSN 0002-9513. PMID 9458786

Heinemann, A.; Jocic, M.; Peskar, B. M.; Holzer, P. (1996-02). "CCK-evoked hyperemia in rat gastric mucosa involves neural mechanisms and nitric oxide". The American Journal of Physiology. 270 (2 Pt 1): G253–258. doi:10.1152/ajpgi.1996.270.2.G253. ISSN 0002-9513. PMID 8779966

Insulin and endothelium

 * King, G. L.; Buzney, S. M.; Kahn, C. R.; Hetu, N.; Buchwald, S.; Macdonald, S. G.; Rand, L. I. (1983-04). "Differential responsiveness to insulin of endothelial and support cells from micro- and macrovessels". The Journal of Clinical Investigation. 71 (4): 974–979. doi:10.1172/jci110852. ISSN 0021-9738. PMC 436955. PMID 6339562
 * *** Zeng, G.; Quon, M. J. (1996-08-15). "Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells". The Journal of Clinical Investigation. 98 (4): 894–898. doi:10.1172/JCI118871. ISSN 0021-9738. PMC 507502. PMID 8770859
 * Zeng, G.; Nystrom, F. H.; Ravichandran, L. V.; Cong, L. N.; Kirby, M.; Mostowski, H.; Quon, M. J. (2000-04-04). "Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells". Circulation. 101 (13): 1539–1545. doi:10.1161/01.cir.101.13.1539. ISSN 1524-4539. PMID 10747347
 * Montagnani, Monica; Ravichandran, Lingamanaidu V.; Chen, Hui; Esposito, Diana L.; Quon, Michael J. (2002-08). "Insulin receptor substrate-1 and phosphoinositide-dependent kinase-1 are required for insulin-stimulated production of nitric oxide in endothelial cells". Molecular Endocrinology (Baltimore, Md.). 16 (8): 1931–1942. doi:10.1210/me.2002-0074. ISSN 0888-8809. PMID 12145346
 * 8039596 24304569 29055722 31063772 9284085

Endothelial dysfunction is observed in morbid obesity only when insulin resistance is present
Vascular problems and HT may precede T2D by realatively long periods

See also:

El Assar, Mariam; Ruiz de Adana, Juan Carlos; Angulo, Javier; Pindado Martínez, María Luz; Hernández Matías, Alberto; Rodríguez-Mañas, Leocadio (2013-10-20). "Preserved endothelial function in human obesity in the absence of insulin resistance". Journal of Translational Medicine. 11: 263. doi:10.1186/1479-5876-11-263. ISSN 1479-5876. PMC 4016214. PMID 24138787

Circulatory adjustment to eating
Vatner, S. F.; Patrick, T. A.; Higgins, C. B.; Franklin, D. (1974-05). "Regional circulatory adjustments to eating and digestion in conscious unrestrained primates". Journal of Applied Physiology. 36 (5): 524–529. doi:10.1152/jappl.1974.36.5.524. ISSN 0021-8987. PMID 4207835

Vatner, S. F.; Franklin, D.; Van Citters, R. L. (1970-07). "Mesenteric vasoactivity associated with eating and digestion in the conscious dog". The American Journal of Physiology. 219 (1): 170–174. doi:10.1152/ajplegacy.1970.219.1.170. ISSN 0002-9513. PMID 4393203

Kvietys, Peter R. (2010). Postprandial Hyperemia. Morgan & Claypool Life Sciences.

Digestive disorders in T2D
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Biopsy studies

 * Pasricha, Pankaj J.; Pehlivanov, Nonko D.; Gomez, Guillermo; Vittal, Harsha; Lurken, Matthew S.; Farrugia, Gianrico (2008-05-30). "Changes in the gastric enteric nervous system and muscle: a case report on two patients with diabetic gastroparesis". BMC gastroenterology. 8: 21. doi:10.1186/1471-230X-8-21. ISSN 1471-230X. PMC 2442096. PMID 18513423
 * Grover, Madhusudan; Farrugia, Gianrico; Lurken, Matthew S.; Bernard, Cheryl E.; Faussone-Pellegrini, Maria Simonetta; Smyrk, Thomas C.; Parkman, Henry P.; Abell, Thomas L.; Snape, William J.; Hasler, William L.; Ünalp-Arida, Aynur (2011-05). "Cellular changes in diabetic and idiopathic gastroparesis". Gastroenterology. 140 (5): 1575–1585.e8. doi:10.1053/j.gastro.2011.01.046. ISSN 1528-0012. PMC 3081914. PMID 21300066
 * Grover, M.; Bernard, C. E.; Pasricha, P. J.; Lurken, M. S.; Faussone-Pellegrini, M. S.; Smyrk, T. C.; Parkman, H. P.; Abell, T. L.; Snape, W. J.; Hasler, W. L.; McCallum, R. W. (2012-06). "Clinical-histological associations in gastroparesis: results from the Gastroparesis Clinical Research Consortium". Neurogastroenterology and Motility: The Official Journal of the European Gastrointestinal Motility Society. 24 (6): 531–539, e249. doi:10.1111/j.1365-2982.2012.01894.x. ISSN 1365-2982. PMC 3353102. PMID 22339929

LOW-GRADE INFLAMMATION FROM https://pubmed.ncbi.nlm.nih.gov/33666873/

7. Dixon JB, O’Brien PE. Obesity and the white blood cell count: changes with sustained weight loss. Obes Surg. 2006;16:251–7.

8. Salman MA, Salman AA, Nafea MA, et al. Study of changes of obesity-related inflammatory cytokines after laparoscopic sleeve gastrectomy. ANZ J Surg. Blackwell Publishing. 2019;89:1265–9.

9. Hagman DK, Larson I, Kuzma JN, et al. The short-term and longterm effects of bariatric/metabolic surgery on subcutaneous adipose tissue inflammation in humans. Metabolism. W.B. Saunders. 2017;70:12–22.

10. Chiappetta S, Schaack HM, Wölnerhannsen B, et al. The impact of obesity and metabolic surgery on chronic inflammation. Obes Surg. Springer New York LLC. 2018;28:3028–40.

11. "Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans". Journal of Lipid Research. 46 (11): 2347–2355. doi:10.1194/jlr.M500294-JLR200. ISSN 0022-2275. PMID 16150820

Spiridonov, V. K.; Vorob'eva, N. F. (2000-03). "The effects of stimulation and lesioning of LIVER? afferent nerves on blood glucose and free fatty acid contents in rats in conditions of changing glycemia". Neuroscience and Behavioral Physiology. 30 (2): 207–211. doi:10.1007/BF02463160. ISSN 0097-0549. PMID 10872732

** Bastard, Jean-Philippe; Maachi, Mustapha; Lagathu, Claire; Kim, Min Ji; Caron, Martine; Vidal, Hubert; Capeau, Jacqueline; Feve, Bruno (2006-03). "Recent advances in the relationship between obesity, inflammation, and insulin resistance". European Cytokine Network. 17 (1): 4–12. ISSN 1148-5493. PMID 16613757 CUENTO REDONDO?

Adipocyte clearance
** MACROPHAGES IN OBESE FAT Weisberg, Stuart P.; McCann, Daniel; Desai, Manisha; Rosenbaum, Michael; Leibel, Rudolph L.; Ferrante, Anthony W. (2003-12). "Obesity is associated with macrophage accumulation in adipose tissue". The Journal of Clinical Investigation. 112 (12): 1796–1808. doi:10.1172/JCI19246. ISSN 0021-9738. PMC 296995. PMID 14679176

** macrophage-specific genes "Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance". The Journal of Clinical Investigation. 112 (12): 1821–1830. doi:10.1172/JCI19451. ISSN 0021-9738. PMC 296998. PMID 14679177

** REVIEW Li, Manna; Qian, Ming; Kyler, Kathy; Xu, Jian (2021). "Adipose Tissue-Endothelial Cell Interactions in Obesity-Induced Endothelial Dysfunction". Frontiers in Cardiovascular Medicine. 8: 681581. doi:10.3389/fcvm.2021.681581. ISSN 2297-055X. PMC 8282205. PMID 34277732

** Alkhouri, Naim; Gornicka, Agnieszka; Berk, Michael P.; Thapaliya, Samjhana; Dixon, Laura J.; Kashyap, Sangeeta; Schauer, Philip R.; Feldstein, Ariel E. (2010-01-29). "Adipocyte apoptosis, a link between obesity, insulin resistance, and hepatic steatosis". The Journal of Biological Chemistry. 285 (5): 3428–3438. doi:10.1074/jbc.M109.074252. ISSN 1083-351X. PMC 2823448. PMID 19940134.

21047928 28954231 28121218 26900135 24795087 23991364 23372170 33826917

Muscle

 * "Insulin Resistance Is Not Sustained Following Denervation in Glycolytic Skeletal Muscle". International Journal of Molecular Sciences. 22 (9): 4913. doi:10.3390/ijms22094913. ISSN 1422-0067. PMC 8125496. PMID 34066429

Training
10.1007/s11357-014-9704-6 10.1016/j.neulet.2010.05.058 10.1016/j.jshs.2016.07.006 27748956 10.1152/ajpheart.1998.274.6.H2053 10.1159/000080759

Postprandial muscle hyperemia
Russell, Ryan D.; Roberts-Thomson, Katherine M.; Hu, Donghua; Greenaway, Timothy; Betik, Andrew C.; Parker, Lewan; Sharman, James E.; Richards, Stephen M.; Rattigan, Stephen; Premilovac, Dino; Wadley, Glenn D. (2021-09-29). "Impaired postprandial skeletal muscle vascular responses to a mixed meal challenge in normoglycaemic people with a parent with type 2 diabetes". Diabetologia. doi:10.1007/s00125-021-05572-7. ISSN 1432-0428. PMID 34590175

Fat tissue
Ye, Jianping (2011-06). "Adipose tissue vascularization: its role in chronic inflammation". Current Diabetes Reports. 11 (3): 203–210. doi:10.1007/s11892-011-0183-1. ISSN 1539-0829. PMC 3119578. PMID 21327583

Paavonsalo, Satu; Hariharan, Sangeetha; Lackman, Madeleine H.; Karaman, Sinem (2020-12-14). "Capillary Rarefaction in Obesity and Metabolic Diseases-Organ-Specificity and Possible Mechanisms". Cells. 9 (12): E2683. doi:10.3390/cells9122683. ISSN 2073-4409. PMC 7764934. PMID 33327460

Brain derived growth factor (BDGF)
17172126 21498417

VISCERAL INNERVATION
Järhult, J.; Falck, B.; Ingemansson, S.; Nobin, A. (1979-01). "The functional importance of sympathetic nerves to the liver and endocrine pancreas". Annals of Surgery. 189 (1): 96–100. doi:10.1097/00000658-197901000-00018. ISSN 0003-4932. PMC 1396948. PMID 365113

Iguchi, A.; Kunoh, Y.; Miura, H.; Uemura, K.; Yatomi, A.; Tamagawa, T.; Kawahara, H.; Sakamoto, N. (1989-12). "Central nervous system control of glycogenolysis and gluconeogenesis in fed and fasted rat liver". Metabolism: Clinical and Experimental. 38 (12): 1216–1221. doi:10.1016/0026-0495(89)90162-5. ISSN 0026-0495. PMID 2574406

Moghimzadeh, E.; Nobin, A.; Rosengren, E. (1982-07). "Adrenergic nerves and receptors in the liver". Brain Research Bulletin. 9 (1–6): 709–714. doi:10.1016/0361-9230(82)90176-9. ISSN 0361-9230. PMID 7172045

Nobin, A.; Baumgarten, H. G.; Falck, B.; Ingemansson, S.; Moghimzadeh, E.; Rosengren, E. (1978-12-29). "Organization of the sympathetic innervation in liver tissue from monkey and man". Cell and Tissue Research. 195 (3): 371–380. doi:10.1007/BF00233883. ISSN 0302-766X. PMID 103622.

Guilherme, Adilson; Henriques, Felipe; Bedard, Alexander H.; Czech, Michael P. (2019-04). "Molecular pathways linking adipose innervation to insulin action in obesity and diabetes mellitus". ''Nature Reviews. Endocrinology''. 15 (4): 207–225. doi:10.1038/s41574-019-0165-y. ISSN 1759-5037. PMC 7073451. PMID 30733616

Neuronal control of microvessels
Rosell, S. (1980). "Neuronal control of microvessels". Annual Review of Physiology. 42: 359–371. doi:10.1146/annurev.ph.42.030180.002043. ISSN 0066-4278. PMID 6157355

Vessels can conduct electric signals (spreading vasodilation)
Welsh, Donald G.; Tran, Cam Ha T.; Hald, Bjorn O.; Sancho, Maria (2018-01-06). "The Conducted Vasomotor Response: Function, Biophysical Basis, and Pharmacological Control". Annual Review of Pharmacology and Toxicology. 58 (1): 391–410. doi:10.1146/annurev-pharmtox-010617-052623. ISSN 0362-1642

Neild, T.O. "CELLULAR COUPLING AND CONDUCTED VASOMOTOR RESPONSES". psu.edu. doi 10.1.1.466.1119.

How fat tissue circulation operates
Ballard, K (1978-07). "Functional characteristics of the microcirculation in white adipose tissue". Microvascular Research. 16 (1): 1–18. doi:10.1016/0026-2862(78)90041-9

Rosell, S.; Belfrage, E. (1979-10). "Blood circulation in adipose tissue". Physiological Reviews. 59 (4): 1078–1104. doi:10.1152/physrev.1979.59.4.1078. ISSN 0031-9333. PMID 386395

Hyperemic response regulation
Murrant, Coral L.; Sarelius, Ingrid H. (2015-11-01). "Local control of blood flow during active hyperaemia: what kinds of integration are important?: Arteriolar dilatation in active hyperaemia". The Journal of Physiology. 593 (21): 4699–4711. doi:10.1113/JP270205. PMC 4626542. PMID 26314391

Postprandial intestinal hyperemia
Gallavan, R. H.; Chou, C. C. (1985-09-01). "Possible mechanisms for the initiation and maintenance of postprandial intestinal hyperemia". The American Journal of Physiology. 249 (3 Pt 1): G301–308. doi:10.1152/ajpgi.1985.249.3.G301. ISSN 0002-9513. PMID 3898869

Precapillary sphincters
Altura, B. M. (1971-10). "Chemical and humoral regulation of blood flow through the precapillary sphincter". Microvascular Research. 3 (4): 361–384. doi:10.1016/0026-2862(71)90039-2. ISSN 0026-2862. PMID 4400475

Adenosine regulation
Jacobson, E. D.; Pawlik, W. W. (1994-10). "Adenosine regulation of mesenteric vasodilation". Gastroenterology. 107 (4): 1168–1180. doi:10.1016/0016-5085(94)90244-5. ISSN 0016-5085. PMID 7926466

Jacobson, E. D.; Pawlik, W. W. (1992-03). "Adenosine mediation of mesenteric blood flow". Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society. 43 (1): 3–19. ISSN 0867-5910. PMID 1450432

Deletion
Jurrissen, Thomas J.; Sheldon, Ryan D.; Gastecki, Michelle L.; Woodford, Makenzie L.; Zidon, Terese M.; Rector, R. Scott; Vieira-Potter, Victoria J.; Padilla, Jaume (2016-04-15). "Ablation of eNOS does not promote adipose tissue inflammation". ''American Journal of Physiology. Regulatory, Integrative and Comparative Physiology''. 310 (8): R744–751. doi:10.1152/ajpregu.00473.2015. ISSN 1522-1490. PMC 4867413. PMID 26864812 Columbia, Missouri

Mohan, Sumathy; Reddick, Robert L.; Musi, Nicolas; Horn, Diane A.; Yan, Bo; Prihoda, Thomas J.; Natarajan, Mohan; Abboud-Werner, Sherry L. (2008-05). "Diabetic eNOS knockout mice develop distinct macro- and microvascular complications". Laboratory Investigation; a Journal of Technical Methods and Pathology. 88 (5): 515–528. doi:10.1038/labinvest.2008.23. ISSN 1530-0307. PMID 18391994

Partial
Wang, Chih-Hong; Li, Feng; Hiller, Sylvia; Kim, Hyung-Suk; Maeda, Nobuyo; Smithies, Oliver; Takahashi, Nobuyuki (2011-02-01). "A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy". Proceedings of the National Academy of Sciences of the United States of America. 108 (5): 2070–2075. doi:10.1073/pnas.1018766108. ISSN 1091-6490. PMC 3033253. PMID 21245338 San Antonio, TX

Austin, Susan A.; Katusic, Zvonimir S. (2020-02). "Partial loss of endothelial nitric oxide leads to increased cerebrovascular beta amyloid". Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism. 40 (2): 392–403. doi:10.1177/0271678X18822474. ISSN 1559-7016. PMC 7370614. PMID 30614363 Rochester, MN

Tan, Xing-Lin; Xue, Yue-Qiang; Ma, Tao; Wang, Xiaofang; Li, Jing Jing; Lan, Lubin; Malik, Kafait U.; McDonald, Michael P.; Dopico, Alejandro M.; Liao, Francesca-Fang (2015-06-24). "Partial eNOS deficiency causes spontaneous thrombotic cerebral infarction, amyloid angiopathy and cognitive impairment". Molecular Neurodegeneration. 10: 24. doi:10.1186/s13024-015-0020-0. ISSN 1750-1326. PMC 4479241. PMID 26104027 Memphis, TN

Didion, Sean P. (2017). "Heterozygous eNOS Deficient Mice as a Model to Examine the Effects of eNOS Haploinsufficiency on the Cerebral Circulation". Journal of Neurology & Neuromedicine. 2 (2): 6–9. ISSN 2572-942X. PMC 5467886. PMID 28616625 Jackson, MS

Chronic L-NAME treatment
31642816 7692445 22814004 12470199 /29621523

Uncoupling
19666465 32363908 22361333 21198553 17545302

29407906 26512245 26111938 25534145

25143378

THBH4
24758136 22215712 21512164

21756052 21554376

Hypoxia
** Ye, J. (2009-01-01). "Emerging role of adipose tissue hypoxia in obesity and insulin resistance". International Journal of Obesity (2005). 33 (1): 54–66. doi:10.1038/ijo.2008.229. ISSN 1476-5497. PMC 2650750. PMID 19050672

Lee, Jong Han; Gao, Zhanguo; Ye, Jianping (2013-05-15). "Regulation of 11β-HSD1 expression during adipose tissue expansion by hypoxia through different activities of NF-κB and HIF-1α". ''American Journal of Physiology. Endocrinology and Metabolism''. 304 (10): E1035–1041. doi:10.1152/ajpendo.00029.2013. ISSN 1522-1555. PMC 3651619. PMID 23512810

He, Qing; Gao, Zhanguo; Yin, Jun; Zhang, Jin; Yun, Zhong; Ye, Jianping (2011-05). "Regulation of HIF-1{alpha} activity in adipose tissue by obesity-associated factors: adipogenesis, insulin, and hypoxia". ''American Journal of Physiology. Endocrinology and Metabolism''. 300 (5): E877–885. doi:10.1152/ajpendo.00626.2010. ISSN 1522-1555. PMC 3093977. PMID 21343542

Aberrant vasoconstriction by insulin
Olver, T. Dylan; Grunewald, Zachary I.; Ghiarone, Thaysa; Restaino, Robert M.; Sales, Allan R. K.; Park, Lauren K.; Thorne, Pamela K.; Ganga, Rama Rao; Emter, Craig A.; Lemon, Peter W. R.; Shoemaker, J. Kevin...and Jaume Padilla (2019-11-01). "Persistent insulin signaling coupled with restricted PI3K activation causes insulin-induced vasoconstriction". ''American Journal of Physiology. Heart and Circulatory Physiology''. 317 (5): H1166–H1172. doi:10.1152/ajpheart.00464.2019. ISSN 1522-1539. PMC 6879917. PMID 31603345 Columbia, Missouri

Patchy vasocostriction?
Peacock, A. J. (1995-11-01). "High altitude pulmonary oedema: who gets it and why?". The European Respiratory Journal. 8 (11): 1819–1821. doi:10.1183/09031936.95.08111819. ISSN 0903-1936. PMID 8620944

Sharma Kandel, Rajan; Mishra, Rohi; Gautam, Jeevan; Alaref, Amer; Hassan, Abdallah; Jahan, Nusrat (2020-09-10). "Patchy Vasoconstriction Versus Inflammation: A Debate in the Pathogenesis of High Altitude Pulmonary Edema". Cureus. 12 (9): e10371. doi:10.7759/cureus.10371. ISSN 2168-8184. PMC 7556690. PMID 33062494

Grazing and snacking
St-Onge, Marie-Pierre; Ard, Jamy; Baskin, Monica L.; Chiuve, Stephanie E.; Johnson, Heather M.; Kris-Etherton, Penny; Varady, Krista (2017-02-28). "Meal Timing and Frequency: Implications for Cardiovascular Disease Prevention: A Scientific Statement From the American Heart Association". Circulation. 135 (9). doi:10.1161/CIR.0000000000000476. ISSN 0009-7322.