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Obesity and its comorbidities

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https://www.ncbi.nlm.nih.gov/books/NBK278973/

General

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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.

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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?

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The expression of eNOS appears to be closely related to insulin action on endothelial cells.[1][2] Furthermore, low epression of eNOS in arterial endothelium has been reported in T2D.[3]

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?

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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.

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The occurence of inflammatory phenomena in tissues from T2 diabetic subjects has been documented for nerve, kidney, liver, muscle, heart,[4] 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, [5][6] Furthermore, clinical signs of gastric wall inflammation, such as grastroparesis, are frequent in diabetic patients.[7]

Foregut (subclinical?) inflammation as a triggering factor in T2D.

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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

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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[8]

Is eNO failure in the liver the cause of hyperglycemia in T2D?

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Does polyfagia lead to proinflammatory foregut overfilling?

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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?

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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?

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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[9] 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?

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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

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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[10]

Does hyperlactatemia reflect irrigation failure in T2D?

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Although not generally reported, hyperlactatemia may accompany obesity and T2D.[11] 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.[12] Although such hyperlactinemia may reflect irrrigation failure,[13] it has been interpreted to unveil the occurence of mitochondrial difunction in T2D.[12] 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

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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

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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.[14][15][16]

Tissue renewal

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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.[17]

Gastric bypass, rapid improvement

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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 [18]

Arterial stiffnes and oxidative stress in obesity:

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  • 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[19]
  • 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[20]

Obesity & endothelial disfunction

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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[21]
  • 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[22]
  • 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[23]

Peristalsis - vagus

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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[24]

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[25]

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[26]

Vagus - nitric

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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[27]

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[28]

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[29]

Insulin and endothelium

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  • 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[30]
  • *** 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[31]
  • 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[32]
  • 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[33]
  • 8039596 24304569 29055722 31063772 9284085

Endothelial dysfunction is observed in morbid obesity only when insulin resistance is present

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Vascular problems and HT may precede T2D by realatively long periods[34]

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[35]

FURTHER READING

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  1. Nitric oxide and mitochondria in metabolic syndrome 2015 https://www.frontiersin.org/articles/10.3389/fphys.2015.00020/full
  2. Hepatic sinusoidal dilatation 2018 https://link.springer.com/article/10.1007/s00261-018-1465-8
  3. PPP1R3C mediates metformin-inhibited hepatic gluconeogenesis 2019 https://pubmed.ncbi.nlm.nih.gov/31181215/
  4. Regulation of hepatic glucose production and AMPK by AICAR but not by metformin depends on drug uptake through the equilibrative nucleoside transporter 1 2018 (SEE INTRODU(CTION) https://pubmed.ncbi.nlm.nih.gov/29962100/
  5. Effect of metformin on fatty acid and glucose metabolism in freshly isolated hepatocytes and on specific gene expression in cultured hepatocytes 2001 https://pubmed.ncbi.nlm.nih.gov/11448453/
  6. The Metformin Mechanism on Gluconeogenesis and AMPK Activation: The Metabolite Perspective 2020 https://pubmed.ncbi.nlm.nih.gov/32375255/
  7. Smooth Muscle Phenotypic Diversity: Effect on Vascular Function and Drug Responses 2017 https://pubmed.ncbi.nlm.nih.gov/28212802/
  8. Regulation of vascular tone: cross-talk between sarcoplasmic reticulum and plasmalemma 1995 https://pubmed.ncbi.nlm.nih.gov/7585320/
  9. The role of calcium in the regulation of normal vascular tone and in arterial hypertension 1999 https://pubmed.ncbi.nlm.nih.gov/10614146/
  10. Endothelium-smooth muscle interactions in blood vessels 1997 https://pubmed.ncbi.nlm.nih.gov/9406674/
  11. El tono vascular, Juan Negrín y López 2006 https://rac.es/ficheros/doc/00405.pdf
  12. Impact of endothelin blockade on acute exercise-induced changes in blood flow and endothelial function in type 2 diabetes mellitus 2014 https://pubmed.ncbi.nlm.nih.gov/24928953/
  13. Isometric Versus Aerobic Training Effects on Vascular Adaptation in Patients with Type 2 Diabetes 2019 https://pubmed.ncbi.nlm.nih.gov/31930828/
  14. Endothelial dysfunction or dysfunctions? Identification of three different FMD responses in males with type 2 diabetes 2008 https://pubmed.ncbi.nlm.nih.gov/18262189/
  15. Exercise intolerance in Type 2 diabetes: is there a cardiovascular contribution? 2018 https://pubmed.ncbi.nlm.nih.gov/29420147/
  16. Individual susceptibility to hypoperfusion and reductions in exercise performance when perfusion pressure is reduced: evidence for vasodilator phenotypes 2014 https://pubmed.ncbi.nlm.nih.gov/24970851/
  17. "Liver-specific inducible nitric-oxide synthase expression is sufficient to cause hepatic insulin resistance and mild hyperglycemia in mice". The Journal of Biological Chemistry. 286 (40): 34959–34975. doi:10.1074/jbc.M110.187666. ISSN 1083-351X. PMC 3186386. PMID 21846719.
  18. "Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status". Circulation Research. 119 (5): 652–665. doi:10.1161/CIRCRESAHA.116.308445. ISSN 1524-4571. PMC 4990459. PMID 27418629
  19. "Metformin: A Novel Weapon Against Inflammation". Frontiers in Pharmacology. 12: 622262. doi:10.3389/fphar.2021.622262. ISSN 1663-9812. PMC 7880161. PMID 33584319
  20. Shaw, Jonathan (2019-04-05). "Raw and Red-Hot"- Could inflammation be the cause of myriad chronic conditions? Harvard Magazine. https://www.harvardmagazine.com/2019/05/inflammation-disease-diet
  21. "Fatty acids and chronic low grade inflammation associated with obesity and the metabolic syndrome". European Journal of Pharmacology. 785: 207–214. doi:10.1016/j.ejphar.2016.04.021. ISSN 1879-0712. PMID 27083551
  22. "Metformin improves skin capillary reactivity in normoglycaemic subjects with the metabolic syndrome". Diabetic Medicine: A Journal of the British Diabetic Association. 24 (3): 272–279. doi:10.1111/j.1464-5491.2007.02082.x. ISSN 0742-3071. PMID 17263761
  23. NEPHROPATHY/eNOS Takahashi, Takamune; Harris, Raymond C. (2014). "Role of endothelial nitric oxide synthase in diabetic nephropathy: lessons from diabetic eNOS knockout mice". Journal of Diabetes Research. 2014: 590541. doi:10.1155/2014/590541. ISSN 2314-6753. PMC 4211249. PMID 25371905 [36]
  24. Lobato, N. S.; Filgueira, F. P.; Akamine, E. H.; Tostes, R. C.; Carvalho, M. H. C.; Fortes, Z. B. (2012-05). "Mechanisms of endothelial dysfunction in obesity-associated hypertension". Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas. 45 (5): 392–400. doi:10.1590/s0100-879x2012007500058. ISSN 1414-431X. PMC 3854291. PMID 22488221[37]
  25. Sukumaran, Vijayakumar; Tsuchimochi, Hirotsugu; Sonobe, Takashi; Shirai, Mikiyasu; Pearson, James T. (2019-06). "Liraglutide Improves Renal Endothelial Function in Obese Zucker Rats on a High-Salt Diet". The Journal of Pharmacology and Experimental Therapeutics. 369 (3): 375–388. doi:10.1124/jpet.118.254821. ISSN 1521-0103. PMID 30910920[38]
  26. "Diet-Induced Obesity Promotes Kidney Endothelial Stiffening and Fibrosis Dependent on the Endothelial Mineralocorticoid Receptor". Hypertension (Dallas, Tex.: 1979). 73 (4): 849–858. doi:10.1161/HYPERTENSIONAHA.118.12198. ISSN 1524-4563. PMC 6448566. PMID 30827147[39]
  27. Yin, Dan-dan; Wang, Qian-chen; Zhou, Xun; Li, Ying (2017). "Endothelial dysfunction in renal arcuate arteries of obese Zucker rats: The roles of nitric oxide, endothelium-derived hyperpolarizing factors, and calcium-activated K+ channels". PloS One. 12 (8): e0183124. doi:10.1371/journal.pone.0183124. ISSN 1932-6203. PMC 5560550. PMID 28817716[40]
      • LIVER Watt, Matthew J.; Miotto, Paula M.; De Nardo, William; Montgomery, Magdalene K. (2019-10-01). "The Liver as an Endocrine Organ-Linking NAFLD and Insulin Resistance". Endocrine Reviews. 40 (5): 1367–1393. doi:10.1210/er.2019-00034. ISSN 1945-7189. PMID 31098621[41]

Circulatory adjustment to eating

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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[42]

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[43]

Kvietys, Peter R. (2010). Postprandial Hyperemia. Morgan & Claypool Life Sciences.[44]

Digestive disorders in T2D

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Biopsy studies

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  • 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[45]
  • 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[46]
  • 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[47]

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 [48]

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 [49]

**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[50] CUENTO REDONDO?

Adipocyte clearance

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** 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 [51]

** 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 [52]

**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 [53]

**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.[54]

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Tissues

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Muscle

[edit]
  • "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 [55]

Training

[edit]

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

[edit]

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[56]

Fat tissue

[edit]

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 [57]

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[58]

Brain derived growth factor (BDGF)

[edit]

17172126 21498417

VISCERAL INNERVATION

[edit]

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[59]

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 [60]

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 [61]

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.[62]

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 [63]

Mesenteric circulation

[edit]

Neuronal control of microvessels

[edit]

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[64]

Vessels can conduct electric signals (spreading vasodilation)

[edit]

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[65]

Neild, T.O. "CELLULAR COUPLING AND CONDUCTED VASOMOTOR RESPONSES". psu.edu. doi 10.1.1.466.1119.[66]

How fat tissue circulation operates

[edit]

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[67]

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[68]

Hyperemic response regulation

[edit]

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[69]

Postprandial intestinal hyperemia

[edit]

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[70]

Precapillary sphincters

[edit]

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[71]

Adenosine regulation

[edit]

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[72]

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[73]

eNOS

[edit]

Deletion

[edit]

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[74] 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[75]

Partial

[edit]

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[76] 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[77] 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[78] 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[79] Jackson, MS

Chronic L-NAME treatment

[edit]

31642816 7692445 22814004 12470199 /29621523

Uncoupling

[edit]

[80] [81] [82] [83] [84]

19666465 32363908 22361333 21198553 17545302


29407906 26512245 26111938 25534145

25143378

THBH4

[edit]

24758136 22215712 21512164

21756052 21554376

Hypoxia

[edit]

**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[85]

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[86]

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[87]

Aberrant vasoconstriction by insulin

[edit]

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 [88]

Patchy vasocostriction?

[edit]

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[89]

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[90]

Grazing and snacking

[edit]

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.[91]

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