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Why enhancing peritoneal oxygenation post-meal may help curtail metabolic syndrome

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Based on the itemization below, this paper suggests that deficient post-meal mesenteric hyperemia may significantly contribute to the early-stage development of visceral fat and systemic inflammation in metabolic disease.

1. Seemingly due to remodeling constraints, adipose tissue growing beyond a certain size develops necrotic and microcirculatory lesions. This compromises organ perfusion, leading to hypoxia, particularly post-meal when blood flow demand normally becomes higher.

2. In metabolic disease sufferers, repeated post-meal hypoxia affecting visceral adipose tissue can trigger a vicious cycle of apoptosis, macrophage recruitment, necrosis, inflammation, and impaired blood flow.

3. The above cycle can lead to the release of toxic substances from overgrown adipose tissue into the bloodstream. This "adipotoxicity" is believed to contribute trigger insulin resistance, hypertension and other systemic manifestations of the disease.

4. Functional stress post-meal can increase the frequency of hypoxic events typically affecting adipose tissue  inside the abdomen. Since post-meal periods are times of high blood flow demand in abdominal organs, strategies to improve peritoneal oxygenation after meals could potentially serve to prevent or treat metabolic syndrome.

5. The above hypothesis aligns with clinical and experimental evidence. If confirmed, it could explain the rapid mitigation of metabolic disease seen after bariatric surgery, exercise, or metformin treatment. This understanding may lead to new therapies focused on enhancing tissue perfusion post-meal in the mesenteric vascular bed.

1.0 Introduction

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You should try to link the different sections a bit more with some “lnking” sentences so that the reading will be more fluid. Figures showing key aspects of the review would help the reader to visualise key concepts.

Obesity-related metabolic disease (ORMD) is a multifaceted clinical syndrome characterized by an elevated body mass index (BMI) alongside one or more clinical manifestations, such as hypertension, glucose intolerance, insulin resistance, systemic inflammation, and dyslipidemia.[1][2][3][4] Furthermore, the development of ORMD is often associated with numerous comorbidities that may include type 2 diabetes (T2D), coronary heart disease, stroke, polycystic ovary disease, low fertility, non-alcoholic fatty liver disease, sleep apnea, nephropathy and retinopathy, among others.[5] 

I would probably give fewer examples here (2 or 3, to include the most and the least common, and to illustrate the range of impact, rather than such a comprehensive list).

Given its wide impact, the syndrome ranks among the most destructive epidemics of our time.[6][7] Reexamining available evidence for novel insights in the pathophysiology of the disorder may lead to novel and better ways to prevent the syndrome and/or treat affected patients.[8][9] Although metabolic syndrome can occasionally develop in lean persons,[10][11] obesity, particularly of the abdominal type,[12] dramatically bolsters the risk of occurrence of the disease.[13] Furthermore, inflammation frequently develops in AT in association with obesity, and this phenomenon has been widely referred to as a determinant step in the early pathogenesis of ORMDs.[14][15][16] 

Numbered sections below examine specific aspects of this review. specific areas related to the hypothesis proposed.

2.0 Adipose tissue dynamics in ORMD

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I think 2.1 to 2.3 can be merged into one larger section, or alternatively, expanded into more detail each, otherwise it reads a little short.

2.1 Adipose tissue is constitutively limited in its capacity for homeostatic growth

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Multiple sources of evidence indicate that AT is inherently limited in its capacity for homeostatic growth.[17][18][19][20] According to this view (often termed "expandability" hypothesis), once a threshold value of tissue expansion is breached within a given site?, the normal structure of the tissue becomes distorted, typically showing an increase in apoptosis,[17][21][18] and capillary rarefaction.[19][22] 

if more apoptosis and less adipogenesis, how does the microvasculature become distorted? I will have to study this better but my understanding was that we would have uncontrolled adipocyte proliferation, leading to a tumour-like vasculature - distorted and inefficient which would result in hypoxia… but if apoptosis occurs concomitantly with less angiogenesis does this not suggest controlled growth

Such a distortion brings about microvascular and endothelial dysfunction within the tissue.[23] 

In this conditions, also the capacity of the tissue to store excess nutrients/lipids is compromised and their spillover and accumulation in other peripheral tissue cause lipotoxicity, chronic inflammation and insulin resistance what in the longterm can lead to development of more deleterious metabolic complications[23][24][25] [26]

2.2 Adipose tissue inflammation and lipotoxicity develop in overeating ORMD-prone individuals

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AT overgrowth occurring in weight-putting individuals having high genetic risk of ORMD is typically accompanied by structural and physiological signs of organ dysfunction, including the development of necrosis, and an elevated release of proinflammatory agents (PIA) in the tissue milieu and their overflow into the general circulation.[24][25][26] Such circulating PIA subsequently disrupts the normal function of many organs and tissues all over the body, causing the status of chronic inflammation that is typical of ORMD.20223680 31240819 

"OMENTAL CD14 and IL-18 were overexpressed in omental adipose tissue compared with the subcutaneous depot, irrespective of the subject's obesity or diabetes status. A significant decrease of LPL, GPD1, and leptin expression was observed in omental tissue, and an inverse correlation between expression of CD14 and IL-18 and that of PPARgamma, LPL, and FABP4 was observed." https://pubmed.ncbi.nlm.nih.gov/18448614/

"inflamed adipose phenotype characterized by tissue macrophage accumulation in crown-like structures"https://pubmed.ncbi.nlm.nih.gov/18566296/ human

In individuals suffering ORMD, two principal inflammatory processes operate in concert to drive disease. The first is systemic low-grade inflammation, which damages the vascular endothelium and causes organ dysfunction. The second is a more aggressive AT inflammation, which contributes to the development of  insulin resistance in pheripheral organs and exacerbates systemic inflammation through the secretion of cytokines and adipokines (PMID: 3944883).

Often associated with obesity, inflamed fat tissue secretes elevated levels of fatty acids and proinflammatory cytokines into the circulation, causing disruption of metabolism, ectopic fat accumulation, insulin resistance in target tissues,39337290 and systemic inflammation.[27] As mentioned above, This course of morbid events has been termed lipotoxicity and identified by many researchers as a priming trigger of ORMD.[20][28][29][18][30] 

could we elucidate which cytokines; this would be important to suggest how those could be used for diagnosis/prognosis, mitigation strategies and possibly personalised treatment?

Proof of lipotoxicity as a pathogenic factor in ORMD may be derived from the fact that removal of a third of mesenteric fat by cryolipolysis has been shown to significantly attenuate insulin resistance by the third month after in a swine model of the metabolic syndrome.36443211 

The removal of 30% of mesenteric fat by cryolipolysis has been demonstrated to dramatically reduce insulin resistance by the third month following in a pig model of the metabolic syndrome, which may provide evidence of lipotoxicity as a pathogenic factor in ORMD.

Basically equivalent results had also been reported in 2018 by an entirely different Amercian group working with baboons as an animal model https://pubmed.ncbi.nlm.nih.gov/29631983/ Improvements in insulin sensitivity in resistant animals by the removal of visceral fat have also been reported in mice 24690289 and rats.10576150 9892227

2.3 Adipose tisse angiogenesis and hypoxia in ORMD 

To accomodate excess nutrient storage, the AT in obese state needs to expand through hyperplasia (increase in adipocyte numbers) and hypetrophia (enlargement of adipocytes size). This requires remodelling of the vasculature which involves angiogenesis.It is knowh that in obesity, the vasculature of the AT is altered and dysfunctional what is associated with the deveplopment of hypoxia (PMID: 39363240). During the AT expansion in obesity, the develpment of blood vessels through the processes of vasculogenesis and angiogenesis can not keep up with the growth of the adipocytes, whichs lead to a decrease of 30 to 40% of blood flow in AT of obese subjects compared to lean controls (PMID: 10905489; PMID: 22451920). In this way the impaired blood supply in the AT causes a reduction in  oxygen pressure, leading to the development of local hypoxia in pockets in the AT (PMID: 23249949). AT hypoxic state leads to an increased secretion of inflammation-related adipokines and a switch from oxidative metabolism to anaerobic glycolysis (PMID: 23303904).

2.4 Hypoxia triggers and sustains adipose tissue inflammation in ORMD

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A plausible rationale is needed to explain why AT becomes inflamed in subjects suffering metabolic disease, i.e., what triggers hypoxia, apoptosis, necrosis, and AT degeneration when the organ grows beyond physiologic limits. Based on clinical and experimental evidence cited throughout this paper, we would like to suggest that the intermittent, daily repetition of moments of high circulatory demand predominantly taking place during the PP lapses may be an important contributor to AT decay and lipotoxicity in the context considered. Several laboratories worldwide have provided evidence suggesting that hypoxia may be the primary cause of AT inflammation and lipotoxicity in unhealthy obesity.[31][32][33][34] Indiana professor Jianping Ye states: "in obesity, capillary density and function fail to meet the demand of AT growth. The failure leads to microcirculation dysfunction from an impaired blood perfusion, which results in a local hypoxia response in AT. The hypoxia response in adipocytes and macrophages is a new cellular basis for the chronic inflammation".[35] 29333574 

hypoxia as the cause https://bear.buckingham.ac.uk/440/ Paul Trayhurn

Aligned with the latter view, for example, mice with reduced adipose vascular density due to the experimental deletion of the gene for vascular endothelial growth factor (VEGF) show adipose hypoxia, apoptosis, inflammation, and metabolic defects when reared on a high-fat diet.[36] Conversely, the induction of VEGF expression in these mice leads to a recovery of adipose vasculature and oxygenation of the tissue, thus showing that metabolic imbalance in the affected mice can be reversed by recovering adipose vessel density.[36] 

Also in experimental mice, 17666485 ABSTRACT "Chronic inflammation and reduced adiponectin are widely observed in the white adipose tissue in obesity. However, the cause of the changes remains to be identified. In this study, we provide experimental evidence that hypoxia occurs in adipose tissue in obese mice and that adipose hypoxia may contribute to the endocrine alterations. The adipose hypoxia was demonstrated by a reduction in the interstitial partial oxygen pressure (Po(2)), an increase in the hypoxia probe signal, and an elevation in expression of the hypoxia response genes in ob/ob mice. The adipose hypoxia was confirmed in dietary obese mice by expression of hypoxia response genes. In the adipose tissue, hypoxia was associated with an increased expression of inflammatory genes and decreased expression of adiponectin. In dietary obese mice, reduction in body weight by calorie restriction was associated with an improvement of oxygenation and a reduction in inflammation. In cell culture, inflammatory cytokines were induced by hypoxia in primary adipocytes and primary macrophages of lean mice. The transcription factor NF-kappaB and the TNF-alpha gene promoter were activated by hypoxia in 3T3-L1 adipocytes and NIH3T3 fibroblasts. In addition, adiponectin expression was reduced by hypoxia, and the reduction was observed in the gene promoter in adipocytes. These data suggest a potential role of hypoxia in the induction of chronic inflammation and inhibition of adiponectin in the adipose tissue in obesity." https://pubmed.ncbi.nlm.nih.gov/17666485/

https://pubmed.ncbi.nlm.nih.gov/17895881/ "we compared body composition, serum inflammatory marker concentrations and the expression of several hypoxia-regulated genes in white adipose tissue derived from lean, dietary-induced obese (DIO) and ob/ob male C57BL/6J mice. We also examined white adipose tissue for the presence of hypoxia using both a pimonidazole-based antibody system and a fiberoptic sensor for real-time pO(2) quantification in vivo. Finally, using cell-specific leukocyte antibodies, we performed immunohistochemistry and flow cytometric analyses to further characterize the cellular nature of adipose inflammation. Results: We determined that obesity in male C57BL/6J mice is associated with increased expression of HIF (hypoxia-inducible factor) isoforms and GLUT-1, and that white adipose tissue hypoxia was present in the obese mice. Immunohistochemistry revealed hypoxic areas to colocalize predominantly with F4/80+ macrophages. Interestingly, CD3+ T cells were present in large numbers within the adipose of both DIO and ob/ob obese mice, and flow cytometry revealed their adipose to possess significantly more CD8+ T cells than their lean cohort. Conclusions: White adipose hypoxia and cytotoxic T-cell invasion are features of obesity in C57BL/6J mice and are potential contributors to their local and generalized inflammatory state."
"Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response "Oxygen partial pressure (AT pO2) and AT temperature in abdominal AT (9 lean and 12 overweight/obese men and women) was measured by direct insertion of a polarographic Clark electrode. Body composition was measured by dual-energy X-ray absorptiometry, and insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. Abdominal subcutaneous tissue was used for staining, quantitative RT-PCR, and chemokine secretion assay. Results: AT pO2 was lower in overweight/obese subjects than lean subjects (47 +/- 10.6 vs. 55 +/- 9.1 mmHg); however, this level of pO2 did not activate the classic hypoxia targets (pyruvate dehydrogenase kinase and vascular endothelial growth factor [VEGF]). AT pO2 was negatively correlated with percent body fat (R = -0.50, P < 0.05). Compared with lean subjects, overweight/obese subjects had 44% lower capillary density and 58% lower VEGF, suggesting AT rarefaction (capillary drop out). This might be due to lower peroxisome proliferator-activated receptor gamma1 and higher collagen VI mRNA expression, which correlated with AT pO2 (P < 0.05). Of clinical importance, AT pO2 negatively correlated with CD68 mRNA and macrophage inflammatory protein 1alpha secretion (R = -0.58, R = -0.79, P < 0.05), suggesting that lower AT pO2 could drive AT inflammation in obesity. Conclusions: Adipose tissue rarefaction might lie upstream of both low AT pO2 and inflammation in obesity. These results suggest novel approaches to treat the dysfunctional AT found in obesity."https://pubmed.ncbi.nlm.nih.gov/19074987/

On the clinical side, however, although capillary dysfunction is known to occur in AT from patients suffering from metabolic syndrome,[35][37] and intermittent hypoxia is believed to play an important role in the pathogenesis of AT inflammation in ORMDs,24755071 direct proof that hypoxia is indeed the prevailing trigger of AT inflammation in ORMD-prone healthy subjects still needs unequivocal confirmation. Hopefully, the theoretical work presented in this paper may contribute to defining novel experimental approaches to tackle uncertainties remaining.25987952

2.5 Functional hyperemia and postprandial hyperemia

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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 unit of time. The rise of blood flow occurring as a consequence of an increase in tissue workload has been termed functional hyperemia (FH).[38][39][40] Functional hyperemia occurring in abdominal and other tissues after food ingestion has been termed postprandial hyperemia .[41] Although mesenteric circulation is broadly regulated by systemic factors such as hemodynamic conditions, the autonomic nervous system, and circulating neurohumoral agents,[42][43] at the capillary level, the rise in blood flow occurring in the PP period appears to be mediated by the local upsurge of vasodilatory signals acting at the vascular endothelial level, such as nitric oxide (NO), adenosine and prostacyclin.[44][45][46] These mediators cause vasodilation, capillary recruitment, and increased blood flow, bringing more oxygen and metabolic fuels to the tissues engaged in digestion, absorption and related processes.

PP hyperemia of long duration (hours-long) has been described to take place in the superior mesenteric (or splanchnic) vascular bed[47], affecting blood flow in the stomach[48], intestine[49], kidney[50], fat tissue[51], and other abdominal organs such as the pancreas[52] and liver[53]. The intensity and duration of PP hyperemia along gut segments will be affected by the amount and composition of meals in a topological way, accompanying digestive bolus transit.[54] PP hyperemia appears to occur every day in normal life following each main meal, thanks to a vasodilatory process seemingly designed to increase the availability of oxygen and nutrients, thus increasing metabolic support to tissues and organs involved in the energetically demanding stages of food digestion, absorption and detoxification.[55] Sections below discuss how the chronic failure of PP hyperemia, occurring as a result of excessive weight gain, brings about the occurrence of repetitive, scattered hypoxic episodes in abdominal fat and perhaps other tissues, leading to the development of clinical signs and metabolic complications of ORMD.

2.6 Repeated postprandial irrigation failure may lead to adipose tissue and systemic inflammation in ORMD-prone individuals

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Failure of PP hyperemia in muscle has been shown to occur in T2D[56], but -befitting the germinal relevance of our theory- also in normoglycemic people with a parent with type 2 diabetes.[57] The idea that PP hyperemic failure may bear a causal relationship with the development of inflammation in ORMD stems from the concurrent finding of histological signs of macrophage recruitment and inflammation in AT from adult obese individuals,[58] as well as in those of otherwise healthy obese children.[59][60] Similarly, such signs of inflammation also take place in fat tissue from obesity-prone mice.[61] Grasping the dynamics of tissue renewal will help understand the link between the occurrence of PP hyperemic failure and inflammation.[62] Every tissue suffers a continuous renewal process whereby senescent cells will die to be replaced by nascent ones in a normally harmonious way; whereby decaying units will be degraded by autolysis, timely followed by the clearing of tissue debris by resident macrophages, all occurring in flawless orchestration at a tonic tempo to avoid overt inflammation. It stands to reason that this non-inflammatory state will only be maintained as long as periods of high tissue workload are synchronously accompanied by adequate rises in blood flow. Conversely, an imbalance between high tissue workload and compensatory hyperemia may persistently occur during postprandial lapses in ORMD-prone, weight-putting individuals, would lead to desynchronization of cell renewal processes, along with elevated macrophage recruitment, local inflammation, and spillover of proinflammatory mediators into the general circulation.[22][63]. Hence, the renewal of swollen adipose tissue entails the offshore escalation of a plethora of interacting functional disturbances resulting in the diverse clinical manifestations of metabolic disease.[64] Defective chemical signaling and abnormal paracrine cross-talk between interacting cells (parenchymal, endothelial and immunocompetent) will thus participate in an entangled process of proinflammatory events initially triggered, in our view, by insufficient postprandial irrigation within the mesenteric vascular bed.[65][66]

2.7 Patchy abdominal tissue inflammation in ORMD

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The degree of circulatory deficit (PP hyperemic failure) here attributed as a trigger of inflammatory complications in ORMD appears to be strong enough to cause scattered hypoxic events and sustained tissue inflammation when chronically occurring, but nevertheless mild enough to avoid an overall breakdown of the organs and tissues involved.[67][68] The detection of a multifocal, patchy distribution of inflammatory lesions in abdominal fat in obese individuals might reflect a wider, underregistered occurrence of this phenomenon. In fact, subclinical forms of patchy necrosis evocative of rhabdomiolysis have been described in clinical situations of microcirculatory dysfunction in the heart[69], gut[70][71], kidney[72], and lungs.[73] Also in the brain, hypoperfusion may lead to diffuse inflammative microiembolization or microinfarcts[74], as thought to take place in Alzheimer's disease.[75] Presence of scattered necrotic lesions in abdominal and other tissues of ORMD patients is not an unusual finding.[76][77] Suggestively enough, relatively mild forms of tissue inflammation have been reported to appear in liver (spotty necrosis)[78] and fat tissue (crown-like inflammatory structures)[79] in obese adiponectin-knockout mice. Also, the well-known appearance of degenerative lesions (amyloid plaques) in B-islets of the endocrine pancreas accompanying failure of insulin secretion could well be a consequence of insufficient irrigation during the PP periods postulated to repeatedly occur every day in ORMD-prone subjects.[80][81] Similar patchy inflammation phenomena occur in the placenta of hypertensive, generally insulin-resistant, pre-eclampsic patients.[82][83] Thus, the above evidence justifies wondering if relatively mild, patchy, chronic inflammation is a frequent phenomenon in ORMD, being responsible for the chronic development of the disease, and whose mitigation by appropriate anti-inflammatory intervention may produce therapeutic effects.

3.0 Postprandial hyperemic failure hypothesis: its adherence to clinical evidence

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Clinical evidence from several clinical paradigms of ORMD appears compatible with our hypothesis. Thus, the swift clinical improvement of metabolic disease and diabetes occurring in obese patients shortly after bariatric surgery, [84][85][86] exercise training,[87][88] metformin treatment,[89] or the administration of antioxidants,[90][91] may conceivably originate from a rapid improvement of microcirculation in relevant tissues, and in the associated functional hypermic responses, including PP hyperemia.[92][93]

4.0 Clinical implications of this proposal

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Clinical implications of this proposal of improving peritoneal oxygenation in the post-prandial lapse

Apart from providing a plausible explanation for the origin of lipotoxicity in ORMD, the hypothesis presented above would predict a preventive or therapeutic effect of the syndrome by experimental or clinical maneuvers designed improve blood circulation and PP hyperemic responses in the mesenteric vascular bed, where lipotoxicity may play a particularly early and powerful pathogenic role for disease development. Choices in this respect may include the prescription of adequately timed interventions favoring PP vasodilatory responses in ORMD-prone subjects. Interestingly, several recent reports on the effect of daily treatment for several weeks with PDE-5 inhibitors (including sildenafil and uldenafil) in patients suffering from ORMD, and/or its experimental correlates have described improvements in clinically relevant parameters such as glycemic control, HbA1C levels, insulin sensitivity, and inflammatory markers.[94][95][96] Equivalent results have also been reported in animal models of metabolic disease.[97][98] Since PDE-5 inhibitors are generally known to promote vasodilation in the mesenteric vascular bed, such gains may partly reflect the occurrence of an improvement in abdominal irrigation and in PP hyperemic responses, whose deficit is postulated here. 

are there public databases that can be exploited to determine if patients that are already taking some of these medications have better outcomes?


Exclusions:

- info about long-term effects (2 or more weeks)

- subcutaneous fat

5.0 Research ahead

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5.0 Conclusion and Perspectives

Non-coding RNA https://pubmed.ncbi.nlm.nih.gov/37547582/ https://pubmed.ncbi.nlm.nih.gov/24741638/

Post-meal hyperoxia? 28607631

Flavonols 29288757

combined treatments CD44 modulation, metformin, semaglutide, BS, etc.

Fibrosis https://pubmed.ncbi.nlm.nih.gov/34752708/


I would split the references and put them immediately after the studies they refer to, instead of all at the end of the sentence.

References

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