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Effects of NEFA unsaturation on their in vivo effects and unbound monomeric behavior. Serum MCP-1 (A), BUN (B), NEFA (C), uNEFA (D), and dsDNA (E) after intraperitoneally administering C16:0 (green), C18:1 (blue), and C18:2 (red) as mentioned below the x axis. Values are at necropsy if moribund or euthanasia at 72 hours. (F1) ITC thermograms of injecting NEFA or solvent (0.34% DMSO for C16:0 and PBS for C18:1 or C18:2) at concentrations mentioned below the NEFA into PBS (pH 7.4) at 37°C, and corresponding enthalpograms (F2) and CMCs (F3) shown as shaded rectangles in the areas where they intersect the x axis. Effect of exogenous albumin (final concentrations of 0.5%) on the cytosolic calcium (Cai) (G) and mitochondrial depolarization (m) (H and I) induced by 100 M of the indicated NEFA added at 100 s. (J and K) Comparison of the dose responses of increase in mitochondrial depolarization (m) after 60 s of addition of different concentration of C18:1 (blue) or C18:2 (red) in acini (J) and HEK293 cells (K). * indicates significant difference (P < 0.05) from the previous lower concentration by paired t test. # indicates a significant difference between C18:2 and C18:1 for that specific concentration on t test.
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Obesity sometimes seems protective in disease. This obesity paradox is predominantly described in reports from the Western Hemisphere during acute illnesses. Since adipose triglyceride composition corresponds to long-term dietary patterns, we performed a meta-analysis modeling the effect of obesity on severity of acute pancreatitis, in the context...
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... LA concentrations in the fat pads of the UFAand SFA-fed ob/ob mice correspondingly matched reports of those in human adipose tissue from Japan [≈40% (25)] and the United States [5% (26)]. By 8 to 14 weeks, the mice averaged 45.5 ± 0.5 g in both groups. CER AP reduced survival to 10% in the UFA group by day 3 versus 90% in the SFA group (P < 0.02; fig. S6). We then simulated the lower cutoff BMI (≤25) associated with SAP in countries with a higher %UFA intake. AP was initiated in UFA-fed mice weighing 20 to 30% less and having 35 to 40% less adipose tissue (Fig. 2, A2 to A4). AP increased serum amylase and lipase similarly in both groups (Fig. 2, B1 and B2) but was worse in the leaner ...
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... induce inflammation and organ failure. LA [0.3% body weight (28, 53, 54)], OA (7), or PA (0.5%) body weight was instilled into the peritoneal cavity to simulate NEFA generated from visceral fat (2 to 10% body weight) lipolysis (64). Unlike LA and OA, there was no increase in circulating cytokines or organ failure (BUN increase) induced by PA (Fig. 6, A and B). The median survival for LA-treated mice was 18 hours and for OA was 64 hours, while the PA group had no adverse outcome over 3 days. Serum NEFA (which are predominantly albumin bound) and unbound NEFA (uNEFA; Fig. 6, C and D) increased significantly only in the LA and OA groups, along with levels of the DAMP and dsDNA (Fig. ...
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... (64). Unlike LA and OA, there was no increase in circulating cytokines or organ failure (BUN increase) induced by PA (Fig. 6, A and B). The median survival for LA-treated mice was 18 hours and for OA was 64 hours, while the PA group had no adverse outcome over 3 days. Serum NEFA (which are predominantly albumin bound) and unbound NEFA (uNEFA; Fig. 6, C and D) increased significantly only in the LA and OA groups, along with levels of the DAMP and dsDNA (Fig. 6E) and a drop in serum albumin consistent with the hypoalbuminemia noted during experimental ( fig. S15, A to C) and clinical SAP (55). This suggested that, unlike PA, both LA and OA with high uNEFA may directly injure cells, ...
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... by PA (Fig. 6, A and B). The median survival for LA-treated mice was 18 hours and for OA was 64 hours, while the PA group had no adverse outcome over 3 days. Serum NEFA (which are predominantly albumin bound) and unbound NEFA (uNEFA; Fig. 6, C and D) increased significantly only in the LA and OA groups, along with levels of the DAMP and dsDNA (Fig. 6E) and a drop in serum albumin consistent with the hypoalbuminemia noted during experimental ( fig. S15, A to C) and clinical SAP (55). This suggested that, unlike PA, both LA and OA with high uNEFA may directly injure cells, triggering DAMP release and downstream inflammation. This would also be consistent with the in vivo AP models ...
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... form in aqueous media. On ITC at 37°C, we noted the critical micellar concentration (CMC) and therefore the aqueous monomeric NEFA concentrations to increase with the number of double bonds (Fig. 6, F1 to F3). The CMCs of PA (C16:0), OA (C18:1), and LA (C18:2) were respectively <8, ≈40, and ≈160 M, which paralleled the uNEFA levels in vivo (Fig. 6D). The calorimetric results were then validated using ultracentrifugation. Both of these methods could be performed at room temperature (23°C; fig. S16) and showed that the nonmicellar NEFA concentrations in the infranatents of 500 M NEFA in PBS (pH 7.4), spun at 10 5 g for 1 hour ( fig. S16, A and B), were similar to the CMCs on ...
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... role of uNEFA in causing biological effects was then studied in cells. Addition of 100 M LA (below CMC) to pancreatic acini caused a larger increase in Cai (Fig. 6G) and m (Fig. 6H) than 100 M OA (above CMC). PA caused no change in these. A total of 0.5% albumin (Alb) completely aborted the Cai increase by both LA and OA and prevented m from progressing (Fig. 6, H and I). This effect of albumin proves that the Cai and m increases were from the uNEFA. It also shows that Cai and m changes result ...
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... role of uNEFA in causing biological effects was then studied in cells. Addition of 100 M LA (below CMC) to pancreatic acini caused a larger increase in Cai (Fig. 6G) and m (Fig. 6H) than 100 M OA (above CMC). PA caused no change in these. A total of 0.5% albumin (Alb) completely aborted the Cai increase by both LA and OA and prevented m from progressing (Fig. 6, H and I). This effect of albumin proves that the Cai and m increases were from the uNEFA. It also shows that Cai and m changes result from distinct ...
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... in causing biological effects was then studied in cells. Addition of 100 M LA (below CMC) to pancreatic acini caused a larger increase in Cai (Fig. 6G) and m (Fig. 6H) than 100 M OA (above CMC). PA caused no change in these. A total of 0.5% albumin (Alb) completely aborted the Cai increase by both LA and OA and prevented m from progressing (Fig. 6, H and I). This effect of albumin proves that the Cai and m increases were from the uNEFA. It also shows that Cai and m changes result from distinct mechanisms of these uNEFA. The sustained m elevation, without progression, despite albumin (Fig. 6, H and I) signifying irreversible uNEFA toxicity, is distinct from the complete reversal of Cai ...
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... (Alb) completely aborted the Cai increase by both LA and OA and prevented m from progressing (Fig. 6, H and I). This effect of albumin proves that the Cai and m increases were from the uNEFA. It also shows that Cai and m changes result from distinct mechanisms of these uNEFA. The sustained m elevation, without progression, despite albumin (Fig. 6, H and I) signifying irreversible uNEFA toxicity, is distinct from the complete reversal of Cai by albumin (Fig. 6G) and explains the cell death noted from LA or OA in previous studies (6). Therefore, the greater Cai and m induced by LA than OA at 100 M (Fig. 6, G and H) may be due to LA's higher CMC (Fig. 6F3) and thus explains the higher ...
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... This effect of albumin proves that the Cai and m increases were from the uNEFA. It also shows that Cai and m changes result from distinct mechanisms of these uNEFA. The sustained m elevation, without progression, despite albumin (Fig. 6, H and I) signifying irreversible uNEFA toxicity, is distinct from the complete reversal of Cai by albumin (Fig. 6G) and explains the cell death noted from LA or OA in previous studies (6). Therefore, the greater Cai and m induced by LA than OA at 100 M (Fig. 6, G and H) may be due to LA's higher CMC (Fig. 6F3) and thus explains the higher uNEFA levels and shorter survival noted in LA-treated mice. We tested this by measuring the dose response of ...
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... of these uNEFA. The sustained m elevation, without progression, despite albumin (Fig. 6, H and I) signifying irreversible uNEFA toxicity, is distinct from the complete reversal of Cai by albumin (Fig. 6G) and explains the cell death noted from LA or OA in previous studies (6). Therefore, the greater Cai and m induced by LA than OA at 100 M (Fig. 6, G and H) may be due to LA's higher CMC (Fig. 6F3) and thus explains the higher uNEFA levels and shorter survival noted in LA-treated mice. We tested this by measuring the dose response of increase in m over baseline , and dsDNA (E) after intraperitoneally administering C16:0 (green), C18:1 (blue), and C18:2 (red) as mentioned below ...
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... 60 s after the addition of LA or OA to acini (Fig. 6J) or human embryonic kidney (HEK) 293 cells (Fig. 6K) to represent the pancreatic and kidney injury in vivo (Fig. 4, D1 to D4, and fig. S9, D1 and D2). Consistent with OA's CMC (≈40 M; Fig. 6F3), m increased over baseline at 50 M OA (*) and then plateaued (Fig. 6, J and K). Similarly, LA's m increased till 100 M and ceased at 200 ...
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... 60 s after the addition of LA or OA to acini (Fig. 6J) or human embryonic kidney (HEK) 293 cells (Fig. 6K) to represent the pancreatic and kidney injury in vivo (Fig. 4, D1 to D4, and fig. S9, D1 and D2). Consistent with OA's CMC (≈40 M; Fig. 6F3), m increased over baseline at 50 M OA (*) and then plateaued (Fig. 6, J and K). Similarly, LA's m increased till 100 M and ceased at 200 M, consistent with its CMC of ≈160 M. While LA's ...
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... 60 s after the addition of LA or OA to acini (Fig. 6J) or human embryonic kidney (HEK) 293 cells (Fig. 6K) to represent the pancreatic and kidney injury in vivo (Fig. 4, D1 to D4, and fig. S9, D1 and D2). Consistent with OA's CMC (≈40 M; Fig. 6F3), m increased over baseline at 50 M OA (*) and then plateaued (Fig. 6, J and K). Similarly, LA's m increased till 100 M and ceased at 200 M, consistent with its CMC of ≈160 M. While LA's m equaled OA's at 50 M, it was more than OA's (#) at concentrations of ≥100 M. LA and OA (60 M), unlike PA, also reduced endothelial barrier integrity ( fig. S15, D and E), potentially explaining the ...
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... of ≥100 M. LA and OA (60 M), unlike PA, also reduced endothelial barrier integrity ( fig. S15, D and E), potentially explaining the hypotension (Fig. 2E1 and fig. S10C) hypothesized to be from vascular leak during SAP (66), along with explaining the hypoalbuminemia ( fig. S15, A to C) (55) in severe AP, and the uNEFA increase noted (Fig. 6D). Overall, these studies cumulatively validate that double bonds increase monomeric long-chain NEFA concentrations and signaling in an aqueous environment, thus enhancing their ...
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... of visceral fat more prone to lipolysis (Figs. 2 and 3), generating higher concentrations of monomeric NEFA (Fig. 6), thus worsening outcomes in leaner populations (Fig. 1). The reverse holds true for SFAs, and this is relevant to studies from Western countries (72) that show AP severity to be independent of intra-abdominal fat amounts even when this fat is above the range in studies from Asian countries (71). This is exemplified by the six studies ...
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... the argument in favor of the genetic or chronic effects of obesity such as insulin resistance and atherosclerosis in explaining these outcomes. The deleterious effects that we note with GTL are also seen with the triglyceride of OA but not with GTP during pancreatitis (5). These along with the deleterious effect of monomeric unsaturated NEFA (Fig. 6), lipase (16)(17)(18), and NEFA elevation (19,20,23), being associated with worse outcomes in other diseases states including COVID-19 (22,24), perhaps support the general relevance of dietary and visceral fat unsaturation in causing the obesity paradox (11)(12)(13)(14)(15). A palmitate-enriched diet in ob/ob mice helped avoid the ...
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Increased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese...
Citations
... 31 Studies have highlighted stark racial differences in the epidemiology of AP as ethnic minorities usually tend to have a greater degree of severity of AP and are associated with an increased risk of adverse outcomes. 21,[32][33][34][35] These subset populations may have less access to education, less access to healthcare, and diminished healthcare coverage, which often leads to a delayed presentation, development of complications, and a more severe clinical course of the disease. 21 Literature reports that Black populations have 2-3 times greater risk of hospitalization secondary to AP compared with their White counterparts. ...
... 21,[32][33][34][35] These subset populations may have less access to education, less access to healthcare, and diminished healthcare coverage, which often leads to a delayed presentation, development of complications, and a more severe clinical course of the disease. 21 Literature reports that Black populations have 2-3 times greater risk of hospitalization secondary to AP compared with their White counterparts. [32][33][34] Blacks have also been noted to have higher rates of readmissions of AP after the index episode. ...
Objective: To identify the influence of body mass index (BMI) on Acute Pancreatitis (AP) hospitalizations in the United States (US). Methods: The National Inpatient Sample was utilized to identify normal weight, overweight and obese AP hospitalizations in the US from 2016–2019 based on BMI. Hospitalization characteristics and outcomes were compared. Results: Between 2016–2019, there were 314,215 (74.7%) obese, 27,005 (6.4%) overweight and 79,380 (18.9%) normal weight AP hospitalizations. Obese AP hospitalizations were younger (51.5 vs 56.5 years, p < 0.0001) compared to the normal weight cohort. However, normal weight AP hospitalizations had a higher proportion of Blacks and Asians compared to the obese subgroup. We also noted a higher all-cause inpatient mortality for normal weight AP hospitalizations (3.4% vs 2.8% vs 1.8%, p < 0.0001) compared to the overweight and obese cohorts, respectively. Furthermore, normal weight AP hospitalizations had a higher proportion of patients with pancreatic pseudocyst formation and pancreatic necrosis compared to the overweight and obese cohorts. The mean length of stay (5.8 vs 8.2 days, p < 0.0001) and mean total healthcare costs ($66,742 vs $82,319, p < 0.0001) were lower for obese compared to normal weight AP hospitalizations. Conclusions: Normal weight AP hospitalizations had higher inpatient mortality and complications compared to obese hospitalizations.
... Hypertriglyceridemia is the third most common cause of AP [13], and clinically, triglyceride-related metabolites are positively associated with the severity of AP [14,15] and pancreatic injury [16]. Lipotoxicity affects not only the multisystem organ failure of AP [17] but also regeneration after AP [18], and lipid saturation is also associated with lipotoxic systemic inflammation [19]; therefore, it is important to identify the lipids involved in the development of AP. We previously reported obviously changed phosphoglycerides and polyunsaturated fatty acyls are probably going to play an important role in the pathogenesis of a cerulein-induced AP mouse model [20]. ...
... In the positive mode, we detected a total of 487 lipids belonging to 8 different lipid subclasses. These included 21 PE-Ps, 19 Figure 4A and Table S6). Figure 4B demonstrates that the analytical process for screening changed representative lipids related to the Orn-SAP procession in the serum. ...
The relationship between the type and intensities of lipids of blood and pancreas and the pathological changes in the pancreas during severe acute pancreatitis (SAP) remains unclear. In our study, we employed a rat model of SAP induced through intraperitoneal ornithine injections. We collected serum and pancreas samples at various time points (0–144 h) for histopathological and biochemical assessments, followed by lipidomic analyses using LC-MS/MS or in situ mass spectrometry imaging (MSI) To discern changes over time or at specific points, we employed time-course and univariate analyses for lipid screening, respectively. Our findings indicated that the peak inflammation in the Orn-SAP model occurred within the 24–30 h timeframe, with evident necrosis emerging from 24 h onwards, followed by regeneration starting at 48 h. Time-course analysis revealed an overall decrease in glycerophospholipids (PEs, PCs, LPEs, LPCs), while CEs exhibited an increase within the pancreas. Univariate analysis unveiled a significant reduction in serum TAGs containing 46–51 carbon atoms at 24 h, and CERs in the pancreas significantly increased at 30 h, compared with 0 h. Moreover, a substantial rise in TAGs containing 56–58 carbon atoms was observed at 144 h, both in serum and pancreas. MSI demonstrated the CERs containing saturated mono-acyl chains of 16 and 18 carbon atoms influenced pancreatic regeneration. Tracing the origin of FFAs hydrolyzed from pancreatic glycerophospholipids and serum TAGs during the early stages of inflammation, as well as FFAs utilized for CEs and CERs synthesis during the repair phase, may yield valuable strategies for diagnosing and managing SAP.
... 5,6 However, previous studies have generated conflicting results: some even suggested the "obesity paradox," implying that obesity has protective effects in severe AP, 7 while others found that obesity does not increase the risk of organ failure. 8 Results regarding the impact of alcoholic etiology on AP outcomes have similarly been mixed. 9 This heterogeneity is largely attributable to significant methodologic constraints that plague both prospective observational studies and retrospective cohort studies that use large administrative databases. ...
... This is the largest prospective observational study in AP that pro- Although obesity has emerged as an important prognostic factor in several acute inflammatory illnesses, including sepsis and COVID-19, 5,16 AP literature has shown mixed results on whether obesity increases the risk of MSOF. 8,11 Most studies analyzed BMI as a dichotomized variable, which simplifies the interpretation of results but also increases the vulnerability to potential confounders and bias. 15 found that the increased risk of death among obese COVID-19positive subjects was seen exclusively among male subjects. ...
Background:
Multisystem organ failure (MSOF) is the most important determinant of mortality in acute pancreatitis (AP). Obesity and alcoholic etiology have been examined as potential risk factors for MSOF, but prior studies have not adequately elucidated their independent effects on the risk of MSOF.
Objective:
We aimed to determine the adjusted effects of body mass index (BMI) and alcoholic etiology on the risk of MSOF in subjects with AP.
Methods:
A prospective observational study of 22 centers from 10 countries was conducted. Patients admitted to an APPRENTICE consortium center with AP between August 2015 and January 2018 were enrolled. Multivariable logistic regression was used to estimate the adjusted effects of BMI, etiology, and other relevant covariates on the risk of MSOF. Models were stratified by sex.
Results:
Among 1544 AP subjects, there was a sex-dependent association between BMI and the risk of MSOF. Increasing BMI was associated with increased odds of MSOF in males (OR 1.10, 95% confidence interval [CI] 1.04-1.15) but not in females (OR 0.98, 95% CI 0.90-1.1). Male subjects with AP, whose BMIs were 30-34 and >35 kg/m2 , had odds ratios of 3.78 (95% CI 1.62-8.83) and 3.44 (95% CI 1.08-9.99), respectively. In females, neither higher grades of obesity nor increasing age increased the risk of MSOF. Alcoholic etiology was independently associated with increased odds of MSOF compared with non-alcohol etiologies (OR 4.17, 95% CI 2.16-8.05).
Conclusion:
Patients with alcoholic etiology and obese men (but not women) are at substantially increased risk of MSOF in AP.
... explained the obesity paradox in their article by suggesting that different visceral triglyceride saturation status could have varying effects on AP severity [51]. According to the results of the subgroup analysis in this meta-analysis, mean age of patients appears to have an effect on adiposity factors and resultantly affects AP severity, which may provide a new thought for the obesity paradox. ...
Background Severe acute pancreatitis (SAP) is a dangerous condition with a high mortality rate. Many studies have found an association between adipokines and the development of SAP, but the results are controversial. Therefore, we performed a meta-analysis of the association of inflammatory adipokines with SAP.
Methods We screened PubMed, EMBASE, Web of Science and Cochrane Library for articles on adipokines and SAP published before March 2, 2023. The quality of the literature was assessed using QUADAS criteria. Standardised mean differences (SMD) with 95% confidence intervals (CI) were calculated to assess the combined effect. Subgroup analysis, sensitivity analysis and publication bias tests were also performed on the information obtained.
Result Fifteen eligible studies included 936 patients with acute pancreatitis (AP). Pooled analysis showed that patients with SAP had significantly higher levels of circulating resistin (SMD = 0.55, 95% CI:0.15 to 0.94, z = 2.70, P = 0.007). The difference in circulating leptin and adiponectin levels between SAP and MAP patients was not significant (SMD = 0.31, 95% CI: -0.11 to 0.73, z = 1.44, P = 0.149 and SMD = -0.07, 95% CI: -0.30 to 0.16, z = 0.57, P = 0.570). Subgroup analyses identified mean age of the patients as possible sources of circulating resistin level heterogeneity.
Conclusion Elevated levels of circulating resistin levels are associated with the development of SAP. Resistin may be potential biomarkers and therapeutic targets for SAP. However, the age of the patient may influence these results.
... Western blotting was also performed using standard methods. 23 After protein denaturation, 20 μg of extracted protein was fractionated on a 10% SDS-PAGE gel and then transferred to a polyvinylidene fluoride (PVDF) membrane with a 0.45-mm pore size (Millipore, MA, USA). The membranes were then blocked in 5% milk at room temperature for 1 h, washed by TBST (Beyotime, Jiangsu, China) and incubated overnight on a shaker at 4°C for the primary antibody. ...
Purpose:
Although paclitaxel is widely used in cancer treatment, severe side effects and drug resistance limit its clinical use. 10-gingerol (10-G) is a natural compound isolated from ginger, which displays anti-inflammatory, antioxidant, and antiproliferative properties. However, the chemotherapy-sensitization effect of 10-G on triple-negative breast cancer (TNBC) has not been fully clarified. This study is aimed at investigating the effect of 10-G on the paclitaxel sensitivity in TNBC, and its underlying mechanism.
Methods:
The study was determined through in vitro and in vivo experiments. Cell viability and proliferation were detected by cell counting kit 8 (CCK-8) and colony formation. To detect cell apoptosis, flow cytometry and TUNEL were used. The expression of proteins was detected by Western blotting and immunohistochemistry. The molecular docking and gene knockout were corroborated by interactions between 10-G and adrenoceptor Beta 2 (ADRB2). The body weight of mice, histopathology and organs (kidney and spleen) coefficients were used to monitor the drug toxicities.
Results:
In vitro, 10-G increased the sensitivity of TNBC cells to paclitaxel, and could synergistically promote the apoptosis of TNBC cells induced by paclitaxel. In combination with molecular docking and lentivirus knockdown studies, ADRB2 was identified as a 10-G binding protein. 10-G inhibited ADRB2 by binding to the active site of ADRB2. Knockdown of ADRB2 reduces the proliferation activity of TNBC cells but also attenuates the sensitizing effects of 10-G to paclitaxel. Western blotting and immunohistochemistry showed that 10-G played an anti-proliferation and chemotherapy-sensitizing role by inhibiting the ADRB2/ERK signal. Toxicity evaluation showed that 10-G would not increase hepatorenal toxicity with paclitaxel.
Conclusion:
This data suggests that 10-G may be used as a new chemotherapeutic synergist in combination with paclitaxel to enhance anticancer activity. The potential value of ADRB2 as a target for improving chemotherapy sensitivity was also emphasized.
... 129 This entry can result from the concurrent release of phospholipases and be exacerbated by FA-induced adipocyte damage. 129 The resulting interaction between lipase and TG can cause fat necrosis of the involved adipocytes [129][130][131][132] and adipocyte receptor-associated TG release. This release, which may be mediated via G-protein coupled protease-activated receptor 4, 133 is triggered proteolytically by trypsin. ...
... 137 Recently, it was demonstrated that the dietary unsaturated/saturated composition determines the FA composition in adipocyte TG, which in turn can influence AP severity. 131 Unsaturated long-chain FAs in a TG make it more prone to lipolysis by pancreatic lipase, whereas saturated long-chain FAs in a TG interfere with this interaction. 131 Therefore, an unsaturated TG may be hydrolyzed more and generate more NEFAs than a saturated TG. ...
... 131 Unsaturated long-chain FAs in a TG make it more prone to lipolysis by pancreatic lipase, whereas saturated long-chain FAs in a TG interfere with this interaction. 131 Therefore, an unsaturated TG may be hydrolyzed more and generate more NEFAs than a saturated TG. Moreover, unsaturated long-chain NEFAs are more aqueous stable than saturated ones. ...
Hypertriglyceridaemia (HTG) is a metabolic disorder, defined when serum or plasma triglyceride concentration (seTG) is >1.7 mM. HTG can be categorized as mild to very severe groups based on the seTG value. The risk of acute pancreatitis (AP), a serious disease with high mortality and without specific therapy, increases with the degree of HTG. Furthermore, even mild or moderate HTG aggravates AP initiated by other important aetiological factors, including alcohol or bile stone. This review briefly summarizes the pathophysiology of HTG, the epidemiology of HTG‐induced AP and the clinically observed effects of HTG on outcomes of AP. Our main focus is to discuss the pathophysiological mechanisms linking HTG to AP. HTG is accompanied by an increased serum fatty acid (FA) concentration, and experimental results have demonstrated that these FAs have the most prominent role in causing the consequences of HTG during AP. FAs inhibit mitochondrial complexes in pancreatic acinar cells, induce pathological elevation of intracellular Ca2+ concentration, cytokine release and tissue injury, and reduce the function of pancreatic ducts. Furthermore, high FA concentrations can induce respiratory, kidney, and cardiovascular failure in AP. All these effects may contribute to the observed increased AP severity and frequent organ failure in patients. Importantly, experimental results suggest that the reduction of FA production by lipase inhibitors can open up new therapeutic options of AP. Overall, investigating the pathophysiology of HTG‐induced AP or AP in the presence of HTG and determining possible treatments are needed.
... Unsaturated fatty acids (UFA) induces acinar cell injury, promotes local pancreatic injury and mediates lipotoxicity as well as progression to multisystem organ failure [13][14][15][16] . Obesity results in a low-grade proin ammatory state, and more pro-in ammatory cytokines are activated during AP [17][18][19][20] . ...
Obese people with acute pancreatitis(AP) have an increased risk of developing severe acute pancreatitis (SAP), which prolongs the length of hospital stay and increases mortality. Thus, elucidation of the mechanisms through which severe acute pancreatitis occurs in obese individuals will provide clues for possible treatment targets. Differences in early events in obese or lean patients with acute pancreatitis have not been conclusively reported. We selected C57BL/6 mice as lean mice models, ob/ob mice or diet induced obese (DIO) mice as obese mice models and then induced experimental AP in mice via injections of caerulein. There were suppressed p-AMPK expressions in the pancreas of obese mice, compared with same age lean C57BL/6 mice, which were further reduced in AP mice models. Obese AP mice were treated using AICAR, a direct AMPK agonist, which prevented pancreatic damage and cell death, suppressed pancreatic enzyme levels in serum, reduced the areas of fat saponification in the peritoneal cavity, prevented injury in other organs and decreased mice mortality rate. Further assays showed that AICAR activates p-AMPK to stabilize pro-caspase-8. Pro-caspase-8 enhances RIPK3 degradation, inhibits pancreatic acinar cell necroptosis and downregulates the release of pancreatic enzymes. Thus, activation of AMPK by AICAR alleviates pancreatic acinar cell necroptosis and converts SAP to mild acute pancreatitis (MAP) in obese mice.
... La señalización continúa e interfiere principalmente con el factor de transcripción lipogénico (PPAR ) y en la proteína que regula los esteroles (SREBP-Ic). Esto hace comprender cómo es que la leptina al incrementar la actividad del AMP-Kinasa (AMP-K) disminuye la activación de la expresión de las enzimas lipogénicas malonil CoA carboxilasa y sintetasa de los AGL "efecto antiestatóico", en otras palabras, bloquea la enzima que sintetiza triglicéridos y ácidos grasos 24 . Al ser disminuido el efecto de los AGL por la leptina, se incrementa la expresión de CoA oxidasa y Carnitil-palmitoil transferasa (CPT-1) enzimas clave en la adecuada oxidación de ácidos grasos en la matriz mitocondrial, lo que hace a la leptina una hormona liporeguladora 25 . ...
Resumen Introducción. La diabesidad es el concepto para describir la ocurrencia de la diabetes y la obesidad de forma simultánea. En el mundo, cada día aumentan las cifras de personas con esta condición y se espera un crecimiento aún más elevado para años futuros, lo cual puede ser catastrófico para la salud individual, salud pública, economía y sistemas sanitarios. Desarrollo. Para comprender el fenómeno de la diabesidad se deben analizar diferentes factores. En este ensayo se plantean dos teorías con las que se puede dar sustento al desarrollo del padecimiento: Teoría del gen ahorrador de energía y desarrollo de genes sociales en el medio obesogénico. Conclusión. La diabesidad es un fenómeno complejo, multi-etiológico, basado en la influencia de las condiciones fisiológicas individuales y las condiciones del contexto social. Palabras clave: obesidad, diabetes, determinantes sociales de la salud. Abstract Introduction. Diabesity is when both diabetes and obesity occur simultaneously. Around the world, the number of people with diabesity is rising every day, and an even steeper climb is expected in the future. This growth in diabesity could have a detrimental effect on both the economy as well as personal health, public health, and healthcare systems. To fully understand the diabesity phenomenon, different factors should be analyzed. In this thesis, two theories will be presented to explain how the disease is manifested: the energy efficiency gene theory, and the social genes theory which will delve into how such genes are developed in an obesogenic environment. Conclusion. Diabesity is a complex, multi-etiological phenomenon, that stems from individual physiological conditions and conditions in the social context.
... Our data showed comparable index hospitalization metrics between both cohorts and equivalent mortality data between the two, despite increased rates of respiratory failure requiring mechanical ventilation. The obesity paradox has been a source of controversy in critically ill patients with sepsis [12,15,26,27]. We found a consistent mortality benefit for patients with class 3 obesity (BMI 35-40) compared with non-obese patients, independent of baseline comorbidities, demographic data, and type of infection. ...
Background: The impact of obesity on the pathogenesis and prognosis of necrotizing soft tissue infections (NSTIs) is unclear. The goal of this study was to characterize differences in NSTI presentation and outcomes by obesity status. Patients and Methods: A retrospective analysis of institutional data for patients diagnosed with NSTIs were identified (n = 619; 2011-2020). Patients were divided based on obesity (body mass index [BMI] ≥ 30 kg/m2) and non-obese (BMI <30 kg/m2). Primary outcomes included NSTI location, micro-organisms, and index hospitalization data. Multiple logistic regression was used to model predictors of in-hospital and 90-day mortality. Results: The obese cohort (n = 390; 63%) had higher rates of congestive heart failure and type 2 diabetes mellitus. There were no differences in length of stay, mortality, or discharge disposition between groups. A higher rate of respiratory failure was observed in the obese versus non-obese group (36.7% vs. 20.9%; p < 0.0005). The obese cohort was associated with perineal (40.8% vs. 27.0%) and torso NSTIs (20.9% vs. 15.8%; p < 0.005) but reduced staphylococcal (19.2% vs. 27.4%; p = 0.02) and group A streptococcal (2.6% vs. 6.5%; p = 0.03) infections, and increased polymicrobial infections. Class 2 obesity was a negative predictor for in-hospital mortality (odds ratio [OR], 0.1; 95% confidence interval [CI], 0.03-0.5) and 90-day mortality (OR, 0.3; 95% CI, 0.1-0.8), when adjusting for demographic data, type of infection, and baseline comorbidities. Conclusions: Necrotizing soft tissue infections in obesity may present with unique distributions and microbial characteristics. Class 2 obesity may exhibit a survival benefit compared with non-obese patients, suggestive of an obesity paradox.
... The term 'obesity paradox' has also been used to explain the improved outcomes and survival noted in persons with mild obesity, as compared to those with normal body weight. 8 The obesity paradox has been documented in disease states as varied as heart failure, communityacquired pneumonia, cancer and kidney disease, and in elderly persons. It is possible that a variant of lipokathexis may be at work here, minimizing the release of potentially harmful lipoproteins into the circulation. ...
'Lipokathexis' is derived from the term 'Lipo' meaning fat and 'kathexis' which means retention. We propose this name for describing a clinical situation wherein despite excessive stores of fat are noted in the body but lower levels of circulating lipids are present in the blood. Different disease conditions that express such a phenotype including Tangier's disease, metabolic healthy obesity and those coming under the domain of obesity paradox have been described in this manuscript. This paper will invoke the readers interest on different facets of lipid metabolism in context of metabolic medicine and explore this concept of "Fat Paradox".
Keywords: Cholesterol, dyslipidemia, hyperlipidemia, LDL cholesterol, myelokathexis, Tangier's disease.
