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Based on published evidence, a hypothesis is proposed for a specific type of microcirculatory déficit -failure of postprandial hyperemic responses affecting abdominal and other tissues- to be primarily responsible for the further development of fat-tissue and systemic inflammation in obesity-related metabolic diseases (ORMD). According to this view, inadequate chemical signaling at the capillary endothelial level, and/or defective vasodilatory responses, postprandially occuring every day in the splanchnic circulation of ORMD-prone individuals would persistently cause scattered hypoxic events in tissues such as abdominal fat which would trigger abnormal macrophage recruitment and local, patchy inflammation, followed by the abnormally high release of pro-inflammatory signals into the circulation. Resulting systemic inflammation has been blamed by many authors for the further development of insulin resistance in target tissues, as well as other manifestations of metabolic disease. This hypothesis may successfully explain clinical evidence of rapid improvement of metabolic disease that occurs as a result of bariatric surgery, exercise training or metformin treatment, and serve as a basis to formulate novel research questions related to the vasodilatory control of capillary function in ORMD and its eventual improvement for prevention or treatment purposes.

Background
Obesity-related metabolic disese (ORMD) is a multisymptom clinical entity characterized by abnormally high body mass-index (BMI) plus one or more accompanying, readly testable pathological signs including high inflammation-marker levels (CRP, HSP, etc) in the blood, hypertension, glucose intolerance, insulin-resistance, and dyslipidemia (high TG/low HDL). Moreover, ORMD is casuistically and pathophysiologically associated with a wide number of comorbidities that include type 2 diabetes (T2D), coronary heart disease, stroke, polycystic ovary disease, low fertility, non-alcoholic fatty liver disease, osteoarthritis, sleep apnoea, gout, gallbladder disease, and microvascular pathologies such as retinopathy and nephropathy.

Globally taken, ORMDs constitutes one of the most devastating epidemics of current times. Reexamining available evidence for new insights in the pathophysiology of the entity may hopefully lead to novel and better ways to prevent and treat patients affected.

Functional hyperemia and PPH
All organs and tissues of the body operate at different intensities at different moments, higher intensities generally involving increased energy expenditure per time unit. Increasing tissular blood circulation in the face of increased workload is generally known as functional hyperemia (FH). FH occurs in many organs and tissues (muscle, CNS, fat tissue, etc) at appropriate times, generally operating by an increase in blood flow (BF) during the lapse of high energy demand; with such high BF being generally mediated by the local surge of prevailing vasodilatory signals (prominently nitric oxide (NO), but also adenosine and prostacyclin) at the vascular endothelial level. FH mediating signals trigger vasodilation, capillary recruitment and increased tissular blood flow per weight unit, thus providing more oxygen and metabolic fuels to the tissue performing intense work. Being an adaptative phenomenon, FH typically occurs in muscle during (rythmic) exercise, heart during induced tachicardia , kidney after food ingestion ,  or particular brain regions or pathways during periods of high neuronal firing.

FH occuring after food ingestion has been termed postprandial hyperemia (PPH). PPH of long duration (hours-long) has been described to occur in skeletal muscle, and importantly also in the superior mesenteric (or splanchnic) vascular bed , affecting blood flow in the stomach , intestine ,  kidney , fat tissue ,  and other abdominal organs such as pancreas   and liver following the ingestion of  food in sufficiently large amounts. Topologically accompanying food bolus transit, the intensity and duration of PPH along each gut segment will depend on meal characteristics of amount and composition.

PPH is believed to occur every day in normal life (following each main meal), appearing to be teleologically designed to increase the provision of oxygen and nutrients to tissues and organs involved in the energetically demanding processes of food digestion, absorption and detoxification.

How PPH failure brings about systemic inflammation
PPH failure in muscle microcirculation has been shown to occur in T2D, but -more significantly- also in normoglycaemic people with a parent with type 2 diabetes. The suggestion that PPH failure can lead to systemic inflammation in ORMD stems from the concurrent finding of histological signs of macrophage recruitment and inflammation in tissues from healthy obese children, as well as from adult obese individuals. Similarly, macrophage accumulation and other signs of inflammation also occur in fat tissue from obesity-prone mice.

Considering the dynamics of tissue renewal may help to understand the causal relationship between PPH failure and inflammation. All tissues undergo renewal processes whereby obsolete cells will die to be replaced by freshly generated ones in a normally harmonious way; decaying units will be degraded by autolysis, together with resident macrophages operating at a "tonic" pace wihout overt inflammation being caused. This non-inflammatory state will only be kept if -when occuring- high tissue workload is accompanied by sufficiently higher microcirculatory blood flow, both events operating smoothly in a geared fashion. The occurence of persistent discordance between increased tissue workload and compensatory hyperemia - as here postulated to postprandially happen every day in ORMD-prone, obese individuals- will likely lead to dysynchronization of cell renewal processes, with overstay and/or overpresence of macrophages, local inflammation and export of proinflammatory mediators into the general circulation. Furthermore, tissue aneutrophic inflammation resulting from sustained PPH-failure in ORMD-prone subjects can become a key triggering factor for the subsequent development of the overt signs of metabolic disease and/or T2D. Defective short-term chemical modulation, as well as paracrine cross-talk mehanisms between parenchymal, endothelial and immune cells participate in cause-effect relations ending in tissue inflammation originally triggered by insufficient postprandial irrigation of relevant organs and tissues such as fat.

Patchy abdominal tissue inflammation in ORMD?
The particular kind of circulatory anomaly (PPH-failure) here proposed to be responsible for the trigger of inflammatory complications of ORMD would be mild enough to not cause overall failure of the organs and tissues involved, but nevertheless lead to hypoxic events and sustained tissue inflammation when chronically occuring. Multifocal, patchy distribution of inflammatory lesions may be the way this borderline scenario occurs. Uneven, subclinical forms of patchy necrosis evocative of rhabdomiolysis or of livedo reticularis have been described to occur in clinical situations of microcirculatory disfunction in the heart, gut , kidney , and lungs. Also in the brain, hypoperfusion may lead to diffuse inflammative microiembolization or microinfarcts, as thought to occur in Alzheimer's disease. The possible development of similar patterns of patchy necrosis in abdominal and other tissues of pathology-afected ORMD patients may also occur. Suggestively enough, relatively mild forms of tissue inflammation have been reported to occur in liver (spotty necrosis) and fat tissue (crown-like inflammatory structures) in obese adiponectin-knockout mice. Also, the well-known appearance of degenerative lesions (amyloid palques) in B-islets of the endocrine pancreas accompanying failure of insulin secretion might well be a consequence of insufficient blood supply during the high-demand postprandial periods repeatedly occuring every day in ORMD-prone subjects. . Similar patchy inflammation phenomena might occur in the placenta of hypertensive, generally insulin-resistant, pre-eclampsic patients. The occurence of relatively mild, patchy, chronic inflammation (rather than overall, acute organ or tissue failure) would explain the slow development of the disease, and its improvement under anti-inflammatory circumstances, as described below.

Why bariatric surgery can rapidly cure diabetes
The popularity gained in recent years by bariatric surgery (BS) to treat morbid obesity has brought about new insights into the pathophysiology of ORMD and its alleviation. Clear evidence of the occurence of gastric inflammation in obesity has been been reported. Thus, histological signs of chronic inflammation have been described in gastric biopsies from insulin-resistant, obese patients undergoing bariatric surgery. Also, clinical signs of gastric wall inflammation, such as grastroparesis, are frequent in diabetic patients.

Interestingly, 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 2-4 weeks after surgery. Explanations offered about the reasons of this effect seem all insufficient.

Our hypothesis offers a novel interpretation: in any of its modalities, BS leads to changing eating habits to ingest smaller meal sizes, which may bring about the suspension of gastric filling (or overfilling) with food. It seems possible that pre-surgery gut inflammation in these patients may have been caused by stretching of gastric walls beyond what these patients can tolerate due to a presumed PPH failure, as here postulated. Thus, the termination of gastric and gut overfilling after BS (caused by eating smaller meals) may lead to alleviation of previously ongoing abdominal organ inflammation including pancreas. Presumably, the limited magnitude of PPH achievable in the ORMD patient becomes sufficient in the postsurgery state, i.e., more balanced with respect to the smaller hyperemic needs posed by the ingestion of smaller meals, thus avoiding hypoxic, proinflammatory events that may have been occuring prior to surgery. Support of this view may be seen in reports that BS leads to a rapid improvement in vasoreactivity.

Why exercise training rapidly improves ORMD
Consistent with our hypothesis, improvement of functional hyperemic responses and endothelial NO synthesis by exercise training may be an important contributor to the improvement of clinical parameters in ORMD, as shown by recent research.

Why metformin improves ORMD and T2D
Also in agreement with the PPH-failure hypothesis, the anti-inflammatory and anti-diabetic effects of metformin treatment may be originated in an improvement of microcirculation and in the capacity for the elaboration of functional hypermic responses, including PPH, as recent research shows.

PPH failure in ORMD: mechanisms involved
Our description of how PPH-failure may trigger disease in ORMD justifies the search for microcirculation-related biochemical lesions occuring at early stages of the syndrome when pathological signs have not yet emerged. Also for the design of microcirculation-related research questions whose answers may lead to improveing PPH-failure to curtail disease development in ORMD. In the short term, vascular tone (and thereby PPH responses) will depend on the relative balance in the action of the most rapidly acting pro- and counter- vasodilatory signals: NO and ROS (reactive oxygen species), respectively. Also the expression of enzymes affecting the balance between these two signals, such as NO synthetase (eNOS) and ROS-degrading enzymes (superoxide dismutase and catalase). In the longer term, however, relevant targets may include pro-trophic endocrine or paracrine factors (insulin, IGFs, VEGFs, HIF) as well as proinflammatory mediators (adipokines, citokines) that play a deleterious role in this context.

PPH failure in ORMD: derived research questions
Sections below briefly describe a few current or novel translational research questions derived from the PPH-failure hypothesis here presented. Some of the answers may prove productive to eventually impinge on improving vascular tone and avoiding PPH-failure in ORMD-prone subjects to curtail disease development:

Genetic studies

 * Are eNOS polymorphisms related to complication risk in ORMD?

An obvious research venue related to our FFH-failure hypothesis is the search for gene polymorphisms of eNOS (the enzyme mainly responsible for the synthesis of NO at the endothelial level) in "healthy obese" vs. obese individuals with metabolic disease. Few reports have been published on the subject, which still warrants further research.


 * Are genetically eNOS-defficient mice a good model to test interventions?

Animal research projects could be designed to investigate to what degree a systemic deficit of nitric oxide production can lead to tissue hypoxia, systemic inflammation, and other signs of metabolic disease would be feasible by using eNOS-deficient, obesity-prone rodents reared under continued, grossly positive energy balance. Heterozygous eNOS-knockout mice could be used for this purpose.

Interventional studies to counteract PPH-failure in ORMD

 * Changing eating habits to ingest many smaller meals each day: would this contribute to ameliorate ORMD?


 * Pharmacological augmentation of NO: could it prevent ORMD complications? Recent evidence supports the beneficial effects of nitrate therapy in obesity and diabetes.


 * Antioxidants
 * Does polyphenolic, flavonoid-type antioxidant treatment help prevent or treat ORMD? Clinical evidence doesn't look very promising, presumably due to relatively poor pharmacodynamic properties of these compounds.
 * Oral vitamin C treatment: a promising approach to prevent ORMD? Preliminary evidence favoring this research venue has recently been reported.

Computational drug-repositioning

 * Could endothelial NO/vascular-tone related variable keywords serve to make testable predictions of drug repositioning to prevent ORMD? Strategies of this type are being explored for the treatment of other diseases, based on the targetting of specific functions and molecular sites.

Testing for PPH: its possible clinical use for personalized treatment
If indeed, PPH-failure proved to be a key early deffect leading to ORMD and its complications, finding ways for testing individuals at risk might serve to allow the testing of different pharmacological options to tprevent or treat the disease in individual patients who may differ in their responses. Recent work using postprandial hyperemia in the forearm as a test may be a step forward in this direction.

Additional notes

 * As well known, a fully displayed case of metabolic syndrome will be characterized by gross overweight (BMI ≥ 35), systemic inflammation ( high blood hsCRP and other inflammation markers), dyslipidemia (highTG and LDL-C, low HDL-C),  hypertension and insulin-resistance and/or T2D. Complex molecular mechanisms beyond the scope of the present mini-review are likely involved in the pathophysiology of such a flowery clinical picture.
 * A certain degree of cooperative, cycling negative feedback appears to occur between inflammation, failure of NO production by eNOS, and a deffective tissue response to insulin. In effect, insulin triggers NO-dependent vasodilation in aortic-rings, and perivascular adipose tissue . In turn, systemic inflammation can be a triggering (or aggravating) factor to the development of insulin resistance,* as shown by the fact that inflammatory cytokines in sufficiently high concentrations can cause insulin-resistance in target cells, both in-vitro*** and in-vivo.*** But Insulin signal itself may be neccessary to the normal expression of eNOS (probably via AMP-activated protein kinase, AMPK), so that once minimally installed, primary insulin resistance may also lead to insufficient NO levels in organs or tissues, especially when tissue workload intensifies and irrigation needs increase. But at the same time, an adequate NO signalling is necessary for a normal tissue response to insulin. Whichever molecular deffect occurs first in ORMD (low NO production, excess ROS, or resistance to insulin action) an impairement of PPH responses would be the resulting outcome.
 * Mesenteric lymphatic vessel dysfunction mechanistically akin to our hypothesis has recently been reported to be responsible for fat-tissue inflammation and insulin resistance in obese mice and humans. Treatment with a COX-2 inhibitor restored normal function in these mice.