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PPH-failure as an early pathogenic event in metabolic syndrome and related diseases

Based on published evidence, a hypothesis is here 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 concept, 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 abdominal fat and probably other tissues, which would trigger abnormal macrophage recruitment. leading to microlocalized, patchy inflammation. In turn, this would cause an abnormally high release of pro-inflammatory signals into the circulation, resulting in systemic inflammation, which has been blamed by many authors for the subsequent development of insulin resistance in target tissues, as well as for other manifestations characterizing metabolic disease. As argued below, th present hypothesis may explain the swift improvement of metabolic disease often occuring after interventions such as bariatric surgery, exercise training or metformin treatment. It may also serve as a basis to formulate novel research related to the vasodilatory control of (mesenteric?) 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 detectable pathological signs including hypertension, glucose intolerance, insulin-resistance, abnormally high inflammation-marker levels (CRP, cytokines, heat shock proteins) in the blood, and dyslipidemia (high TG/low HDL). 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 constitute 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 affected patients. The present review aims to provide a concise, unifying, ontogenic view of the condition, indicating how a particular kind of circulatory failure (faulty postprandial hyperemia) may constitute an early causative trigger to the further development of the disease. Sections below explore the pathophysiological mechanisms involved in the hypothesis, its plausibility in the light of clinical evidence, and its relevance for the design of future research in the field.

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 has been termed 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. Such high BF is commonly mediated by the local upsurge of vasodilatory signals prevailing at the vascular endothelial level, such as nitric oxide (NO), adenosine and prostacyclin. FH mediators trigger vasodilation, capillary recruitment and increased tissular blood flow, thus providing more oxygen and metabolic fuels to the tissue performing intense work. Being adaptative in its nature, FH occurs in varous organs, including muscle during (rythmic) exercise, heart muscle during tachicardia , kidney after food ingestion , or in 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. The intensity and duration of PPH along gut segments will be affected by the amount and composition of meals in a topological way, accompanying digestive bolus transit.

PPH appears to occur every day in normal life following each main meal, thanks to a vasodilatory process seemingly designed to increase the provision of oxygen and nutrients to tissues and organs involved in the energetically demanding stages of food digestion, absorption and detoxification. An explanation is offered below as to how chronic failure of PPH (of whatever molecular cause) will develop as a result of excesive weight gain, resulting in the iteration of scattered hypoxic episodes in abdominal fat and perhaps other tissues, leading to the development of clinical signs and complications which are frequent in ORMD.

How PPH failure brings about systemic inflammation
PPH failure in muscle 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 arises from the finding of concurrent histological signs of macrophage recruitment and inflammation in tissues from adult obese individuals, as well as in those of otherwise healthy obese children. Similarly, macrophage accumulation and other signs of inflammation also occur in fat tissue from obesity-prone mice. Grasping the dynamics of tissue renewal will help understand the link between the occurrence of 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 without overt inflammation. This non-inflammatory state will only be maintained if, when occurring, high tissue workload is accompanied by sufficiently higher circulatory blood flow, both events operating smoothly in a synchronous fashion. The occurrence of persistent discordance between increased tissue workload and compensatory hyperemia (as here posited 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, tissues renewed under such an inflammatory state will likely add further functional disturbances contributing to the subsequent development of the overt signs of metabolic disease and/or T2D. Defective short-term chemical modulation, as well as abnormal paracrine cross-talk between interacting cells (parenchymal, endothelial and immune) probably participate in cause-effect relations resultying in local and systemic inflammation, originally triggered by insufficient postprandial irrigation of relevant organs and tissues, including abdominal fat.

Patchy abdominal tissue inflammation in ORMD?
The degree of circulatory deficit (PPH-failure) here blamed for the trigger of inflammatory complications of ORMD appears to -nevertheless- be mild enough to not cause overall failure of the organs and tissues involved, but strong enough to derive in the occurrence of scattered hypoxic events and sustained tissue inflammation when chronically occuring. The detection of multifocal, patchy distribution of inflammatory lesions in abdomnal fat from obese individuals may reflect such a course of events. 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, gut24496304 , kidney , and lungs. Also in the brain, hypoperfusion may lead to diffuse inflammative microiembolization or microinfarcts, as thought to occur in Alzheimer's disease. Presence of patchy necrotic lesions in abdominal and other tissues of symptomatic ORMD patients is not an unusual finding. 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 chronic development of the disease, and its improvement under anti-inflammatory circumstances.

PPH-failure hypothesis: its adherence to clinical paradigmas of ORMD
Clinical signs of metabolic disease often improve within days of surgical or nutritional procedures thought to decrease splanchnic oxygen demand by reducing nutrient load.

Why bariatric surgery can rapidly cure diabetes

The popularity gained in recent years by bariatric surgery (BS) to treat morbid obesity has provided opportunities to gain new insights into the pathophysiology of ORMD and its possible alleviation paths. 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 patients undergoing bariatric surgery, Moreover, clinical signs of gastric wall inflammation, such as grastroparesis, are frequent in diabetic patients. Once performed, bariatric surgery often leads to a rapid improvement of glycemic control in T2 diabetic patients, the effect becoming dramatically evident as early as 2-4 weeks after surgery. BS in any of its modalities leads to changing eating habits to ingest smaller meal sizes, which may bring about the suspension of gastric filling (or overfilling) with food. Thus, the interruption of gastric and gut overfilling after BS due to eating smaller meals may lead to alleviation of previously ongoing abdominal organ diabetogenic inflammation Presumably, the magnitude of PPH achievable after BS will be more balanced with respect to needs, and sufficient to avoid hypoxic, proinflammatory events that may have been priorly occuring. The improvement or cure of diabetes often reported shortly after BS may be considered circumstantial evidence that systemic inflammation originating from insufficient PPH to meet the irrigation needs imposed by the repeated daily ingestion of regular (or even large, as usual in T2D hyperphagia) meal sizes may have been a determining factor leading to insulin-resistance and poor insulin secretion in these patients. Furthermore, such improvement seems causally related to a rapid improvement in vasoreactivity.

Why exercise training rapidly improves ORMD
Improvement of hyperemic responses and endothelial NO synthesis by exercise training may be an important contributor to the improvement of clinical parameters in ORMD. Exercise training also reduces CRP in individuals with MS 28847205 22691465.

Why metformin improves ORMD and T2D
Available evidence would support the notion that 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.

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PPH failure in ORMD: mechanisms involved
The above description of how PPH-failure may trigger disease in ORMD justifies the search for biochemical lesions detected at early stages of the syndrome and their possible interaction to produce failing vasodilatory postprandial responses, and the identification of research venues that may help in the prevention of ORMD complications and/or treatment.

At any given time, vascular tone (and thereby PPH responses) will depend on the relative balance in the action of pro- and counter- vasodilatory signals, the most rapidly acting of which appear to be NO and ROS, respectively. Despite this, several other molecular entities are known or presumed to participate in the regulation of microvascular tone, among these the expression of relevant genes in vascular system cells (typically eNOS), pro-trophic endocrine or paracrine factors (insulin, IGFs, VEGFs, HIF) appear to favor vascular functionality and homeostasis, while excess ROS and proinflammatory mediators would play a deleterious role in the context referred.

PPH failure in ORMD: derived research questions
Sections below briefly describe some 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 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
 * Do flavonoid-type antioxidant treatments help prevent ORMD?
 * Oral vitamin C treatment: a promising approach to prevent ORMD?

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.