Prolonged Obesity Research Articles

A systematic review and meta-analysis combining adolescent and adult data to evaluate weight loss and the effect of age following the laparoscopic sleeve gastrectomy.

Obesity is a grave concern within the United States, resulting in lost productivity, increased medical costs, and comorbidities with lifelong repercussions. The laparoscopic sleeve gastrectomy is a treatment option for obesity. The following meta-analysis sought to combine adolescent and adult literature to determine the overall effect of the sleeve gastrectomy on weight loss, to evaluate the effect of age at the time of surgery on weight loss, and to describe and explore variation in weight loss by sample characteristics. Overall weight loss was assessed at proximal and distal points, a dichotomous moderator variable analysis was conducted with subjects ≤21 years of age and >21 years of age, and a meta-regression assessing % male, % female, and baseline BMI was conducted to assess moderator variables. The laparoscopic sleeve gastrectomy was effective at facilitating weight loss with effect sizes varying from 0.916 to2.816. Age, biological sex, and baseline BMI were not found to have an impact on weight loss. The clinical consequences of prolonged obesity are evident and earlier intervention may be justified to counter the long-term effects caused by obesity related comorbidities. Standardized reporting of comorbidities and the effect of bariatric surgery on comorbid conditions is essential to allow further analysis.

Krüppel-like factor 4 in transcriptional control of the three unique isoforms of Agouti-related peptide in mice.

Agouti-related peptide (AgRP/Agrp) within the hypothalamic arcuate nucleus (ARC) contributes to the control of energy balance, and dysregulated Agrp may contribute to metabolic adaptation during prolonged obesity. In mice, three isoforms of Agrp are encoded via distinct first exons. Agrp-A (ENSMUST00000005849.11) contributed 95% of total Agrp in mouse ARC, whereas Agrp-B (ENSMUST00000194654.2) dominated in placenta (73%). Conditional deletion of Klf4 from Agrp-expressing cells (Klf4Agrp-KO mice) reduced Agrp mRNA and increased energy expenditure but had no effects on food intake or the relative abundance of Agrp isoforms in the ARC. Chronic high-fat diet feeding masked these effects of Klf4 deletion, highlighting the context-dependent contribution of KLF4 to Agrp control. In the GT1-7 mouse hypothalamic cell culture model, which expresses all three isoforms of Agrp (including Agrp-C, ENSMUST00000194091.6), inhibition of extracellular signal-regulated kinase (ERK) simultaneously increased KLF4 binding to the Agrp promoter and stimulated Agrp expression. In addition, siRNA-mediated knockdown of Klf4 reduced expression of Agrp. We conclude that the expression of individual isoforms of Agrp in the mouse is dependent upon cell type and that KLF4 directly promotes the transcription of Agrp via a mechanism that is superseded during obesity.NEW & NOTEWORTHY In mice, three distinct isoforms of Agouti-related peptide are encoded via distinct first exons. In the arcuate nucleus of the hypothalamus, Krüppel-like factor 4 stimulates transcription of the dominant isoform in lean mice, but this mechanism is altered during diet-induced obesity.

272-LB: Obesity-Induced Mitochondrial Fragmentation in White Adipocytes Is Controlled by the Small GTPase RalA

Mitochondrial dysfunction has been implicated in the development of obesity, insulin resistance and fatty liver disease. Here we report that mitochondria undergo fragmentation and reduced oxidative capacity specifically in inguinal white adipose tissue after high fat diet, and that this process is regulated by the small GTPase RalA. RalA mRNA, protein and GTP binding activity are increased in inguinal white adipose tissue after HFD feeding. Targeted deletion of Rala in white adipocytes prevents the obesity-dependent fragmentation of mitochondria, and produces mice who are resistant to HFD-induced weight gain via increased energy expenditure, as well as improvements in glucose homeostasis and liver metabolism. In vitro studies revealed that RalA suppresses mitochondrial oxidative function in adipocytes by increasing fission through reversing the inhibitory phosphorylation of the mitochondrial fission protein Drp1. This reduced phosphorylation results from the recruitment of the regulatory subunit of protein phosphatase PP2A, which acts as a bona fide effector of RalA, leading to the specific dephosphorylation of the inhibitory Ser637 residue on Drp1, rendering the protein active. Thus, RalA plays a key role in repressing energy expenditure in obese adipose tissue through maintaining mitochondrial fission, contributing to weight gain and related metabolic dysfunction, including glucose intolerance and fatty liver, and may explain in part how energy expenditure is repressed in prolonged obesity. Disclosure W. Xia: None. A. Saltiel: Board Member; Elgia Therapeutics. P. Veeragandham: None. Y. Cao: None. Y. Xu: None. T. E. Rhyne: None. Y. Jones: None. R. T. Yu: None. M. Rydén: Advisory Panel; Boehringer-Ingelheim, Eli Lilly and Company, Consultant; Sigrid Therapeutics, Other Relationship; Novo Nordisk Foundation, Speaker's Bureau; Sanofi, Novo Nordisk. M. Wabitsch: None.

Abstract 114: Metabolic Adaptation During Obesity Is Associated With G Protein Switching By The Angiotensin At1a Receptor In Agrp Neurons

Obesity represents the single greatest impediment to continued improvements in hypertension and cardiovascular disease. Prolonged obesity is associated with “Resting Metabolic Rate (RMR) adaptation” (ie, reduced RMR relative to body composition), and RMR adaptation is proposed to explain resistance to weight loss / weight maintenance after obesity is established. Previously we showed that angiotensin II (ANG) Agtr1a (AT1A) receptors expressed in Agouti-related peptide (AgRP) neurons of the hypothalamic arcuate nucleus (ARC) are required for integrative control of RMR. We hypothesize that changes in AT1A signaling in AgRP cells underlie the development of RMR adaptation. ARC slices from mice expressing tdTomato in AgRP cells ( Agrp -Cre x Ai9) were used for cell-attached voltage clamp recording of AgRP neurons. ANG inhibited ~33% of AgRP neurons via an AT1A-dependent mechanism (deemed a “Type 1i” response, which was inhibitable by losartan (LOS) or genetic deletion of AT1A; Firing rate; aCSF:0.85 ± 0.03 vs ANG:0.20 ± 0.04 vs ANG+LOS:0.91 ± 0.11 Hz, p<0.05) that was also blocked by the Gαi inhibitor, pertussis toxin (PTX), but not by the Gαq inhibitor, BIM-46187 (Δ Firing rate: PTX: -0.39 ± 0.09 Hz, p<0.05 vs BIM: 0.10 ± 0.09 Hz). After 10 weeks of high-fat feeding, roughly half of Type 1 cells exhibited a spontaneous switch from the ANG/AT1A-mediated inhibitory (Type 1i) response to an ANG/AT1A-mediated stimulatory response (“Type 1s”; Firing rate; aCSF: 0.86 ± 0.03 vs ANG:1.10 ± 0.12 vs ANG+LOS:0.82 ± 0.03 Hz, p<0.05), which was blocked by BIM-46187, but not by PTX (Δ Firing rate: PTX: 0.07 ± 0.06 Hz vs BIM: 0.49 ± 0.06 Hz, p<0.05). AAV delivery of Cre-inducible DREADDs into the ARC of lean Agtr1a -Cre mice was then used to study the effects of Gαi vs Gαq signaling in Type 1 AgRP cells upon RMR control. Activation of the Gαi-coupled hM4Di DREADD in AT1A-expressing cells of the ARC was sufficient to increase RMR (+25% from baseline, n=8-10, p<0.05), but activation of a Gαq-coupled DREADD had no effect. We conclude (i) that the AT1A receptor is expressed by a unique subtype of AgRP neuron; (ii) that inhibitory AT1A-Gαi signaling in the Type 1 AgRP cell stimulates RMR; and (iii) that loss of AT1A-Gαi coupling in these cells is sufficient to explain obesity-associated RMR adaptation.

Altered ERK‐mediated control of AgRP and metabolic rate during obesity

Adaptation of resting metabolic rate (RMR) contributes to the maintenance of human obesity, yet RMR control and how this system changes during obesity remains poorly defined. Desensitization of the brain to leptin has been proposed to contribute. Leptin normally suppresses Agouti‐related peptide (AgRP) expression in the arcuate nucleus of the hypothalamus (ARC) to disinhibit (increase) melanocortin‐mediated RMR stimulation. Diet‐induced obesity (DIO) increases leptin, but paradoxically exaggerates Agrp expression and causes RMR adaptation. Thus, something connecting leptin to Agrp control becomes dysfunctional during DIO. Our previous data indicate that within the ARC, disruption in the extracellular signal‐regulated kinase (ERK) cascade occurs during DIO. ERK normally phosphorylates Krüppel‐like factor 4 (KLF4), inactivating it. As KLF4 binds to the AgRP promoter to increase transcription, its inactivation results in reduced Agrp expression. We hypothesize that this mechanism becomes dysfunctional within AgRP neurons during DIO, such that KLF4 binding to the AgRP promoter increases despite increased ERK activity.Mouse hypothalamic GT1‐7 cells (model of AgRP neurons) were treated with leptin (1 uM, 15 min or 1 hr) and pERK/ERK ratio was measured by Simple WES and Agrp mRNA expression via qPCR, respectively. Leptin was given to chow‐fed adult mice (2 ug/g ip 30 min) and ARC pERK/ERK ratio was measured, as well as RMR assessed by respirometry. To examine consequences of ERK or KLF4 disruption upon cardiometabolic phenotypes, mice harboring a conditional version of endogenous Mapk1 or Klf4 were crossed with mice expressing Cre via the Agrp locus.In GT1‐7 cells, leptin increased pERK/ERK ratio (1 uM, 15 min leptin n=3, +89% vs vehicle n=2, p<0.05) and suppressed Agrp expression (1 uM, 1 hr leptin n=2, ‐54.1% vs vehicle n=6, p<0.05). In chow‐fed adult mice, leptin injection caused an increase in the ARC pERK/ERK ratio (2 ug/g ip 30 min leptin n=11, +43.8% vs saline n=9, p<0.05). Additionally, leptin stimulated RMR in adult‐chow fed mice (1 ug/g ip leptin n=8, 16.5‐fold of vehicle n=8, p<0.05). DIO caused increases in endogenous plasma leptin and an increase in the ARC pERK/ERK ratio (High Fat Diet (HFD; n=5), +54.4% vs chow n=4, p<0.05), but ARC Agrp expression was not suppressed (HFD n=4, 1.62 fold of chow n=4, p<0.05). There was a possible exaggeration of weight gain in Agrp‐Cre+, Mapk1F/F mice compared to controls following HFD (KOs n=2, +16.8% vs controls n=3). In contrast, weight gain was possibly attenuated in Agrp‐Cre+, Klf4F/F mice compared to controls following HFD (KO n=1, ‐10.7% vs controls n=2). RMR was higher in chow‐fed Agrp‐Cre+, Klf4F/F mice compared to controls (KOs n=5 +8.3% vs controls n=7, p<0.05) and may be exaggerated following HFD (KO n=1 +13.0% vs controls n=3). Together, these findings suggest that ERK and KLF4 within AgRP neurons appear to contribute to the control of AgRP and thus RMR. These findings may identify ERK control of KLF4 and KLF4 as a potential therapeutic target to maintain/restore RMR control after prolonged obesity.

Microbiota's Role in Diet-Driven Alterations in Food Intake: Satiety, Energy Balance, and Reward.

The gut microbiota plays a key role in modulating host physiology and behavior, particularly feeding behavior and energy homeostasis. There is accumulating evidence demonstrating a role for gut microbiota in the etiology of obesity. In human and rodent studies, obesity and high-energy feeding are most consistently found to be associated with decreased bacterial diversity, changes in main phyla relative abundances and increased presence of pro-inflammatory products. Diet-associated alterations in microbiome composition are linked with weight gain, adiposity, and changes in ingestive behavior. There are multiple pathways through which the microbiome influences food intake. This review discusses these pathways, including peripheral mechanisms such as the regulation of gut satiety peptide release and alterations in leptin and cholecystokinin signaling along the vagus nerve, as well as central mechanisms, such as the modulation of hypothalamic neuroinflammation and alterations in reward signaling. Most research currently focuses on determining the role of the microbiome in the development of obesity and using microbiome manipulation to prevent diet-induced increase in food intake. More studies are necessary to determine whether microbiome manipulation after prolonged energy-dense diet exposure and obesity can reduce intake and promote meaningful weight loss.

Recent Advances in Hypertension: Intersection of Metabolic and Blood Pressure Regulatory Circuits in the Central Nervous System.

Obesity represents the single greatest ongoing roadblock to improving cardiovascular health. Prolonged obesity is associated with fundamental changes in the integrative control of energy balance, including the development of selective leptin resistance, which is thought to contribute to obesity-associated hypertension, and adaptation of resting metabolic rate (RMR) when excess weight is reduced. Leptin and the melanocortin system within the hypothalamus contribute to the control of both energy balance and blood pressure. While the development of drugs to stimulate RMR and thereby reverse obesity through activation of the melanocortin system has been pursued, most of the resulting compounds simultaneously cause hypertension. Evidence supports the concept that although feeding behaviors, RMR, and blood pressure are controlled through mechanisms that utilize similar molecular mediators, these mechanisms exist in anatomically dissociable networks. New evidence supports a major change in molecular signaling within AgRP (Agouti-related peptide) neurons of the arcuate nucleus of the hypothalamus during prolonged obesity and the existence of multiple distinct subtypes of AgRP neurons that individually contribute to control of feeding, RMR, or blood pressure. Finally, ongoing work by our laboratory and others support a unique role for AT1 (angiotensin II type 1 receptor) within one specific subtype of AgRP neuron for the control of RMR. We propose that understanding the unique biology of the AT1-expressing, RMR-controlling subtype of AgRP neurons will help to resolve the selective dysfunctions in RMR control that develop during prolonged obesity and potentially point toward novel druggable antiobesity targets that will not simultaneously cause hypertension.

Obesity, kidney dysfunction, and inflammation: interactions in hypertension.

Obesity contributes 65-75% of the risk for human primary (essential) hypertension (HT) which is a major driver of cardiovascular and kidney diseases. Kidney dysfunction, associated with increased renal sodium reabsorption and compensatory glomerular hyperfiltration, plays a key role in initiating obesity-HT and target organ injury. Mediators of kidney dysfunction and increased blood pressure include (i) elevated renal sympathetic nerve activity (RSNA); (ii) increased antinatriuretic hormones such as angiotensin II and aldosterone; (iii) relative deficiency of natriuretic hormones; (iv) renal compression by fat in and around the kidneys; and (v) activation of innate and adaptive immune cells that invade tissues throughout the body, producing inflammatory cytokines/chemokines that contribute to vascular and target organ injury, and exacerbate HT. These neurohormonal, renal, and inflammatory mechanisms of obesity-HT are interdependent. For example, excess adiposity increases the adipocyte-derived cytokine leptin which increases RSNA by stimulating the central nervous system proopiomelanocortin-melanocortin 4 receptor pathway. Excess visceral, perirenal and renal sinus fat compress the kidneys which, along with increased RSNA, contribute to renin-angiotensin-aldosterone system activation, although obesity may also activate mineralocorticoid receptors independent of aldosterone. Prolonged obesity, HT, metabolic abnormalities, and inflammation cause progressive renal injury, making HT more resistant to therapy and often requiring multiple antihypertensive drugs and concurrent treatment of dyslipidaemia, insulin resistance, diabetes, and inflammation. More effective anti-obesity drugs are needed to prevent the cascade of cardiorenal, metabolic, and immune disorders that threaten to overwhelm health care systems as obesity prevalence continues to increase.

Abstract MP47: Cardiac Compensation And Altered CREB/ERK Signaling Within The Arcuate Nucleus In The C57BL/6J Mouse Model Of Selective Leptin Resistance

Prolonged obesity causes “selective leptin resistance” (SLR), in which cardiovascular responses to leptin are intact but metabolic responses are lost. High fat diet (HFD) for 10 weeks causes SLR in C57BL/6J mice, as it attenuates metabolic (adipose) sympathetic nervous activity (SNA) responses to leptin but has no effect on cardiovascular SNA responses. Using single-nucleus RNAsequencing, we recently discovered disruption of leptin and CREB signaling specifically in Agouti-related peptide ( Agrp ) neurons of the arcuate nucleus of the hypothalamus (ARC) after 10-week HFD. Because C57BL/6J mice are generally resistant to diet-induced changes in blood pressure (BP), one goal of this study was to examine BP in this model. Further, we sought to examine effects of prolonged HFD on CREB signaling and Agrp mRNA within the ARC. Male C57BL/6J mice were maintained on chow (2920x) or HFD (D12451) from 8-18 weeks of age. Intake behaviors were studied in metabolic cages and bomb calorimetry; body composition via nuclear magnetic resonance; BP and HR via radiotelemetry; and cardiac function via echocardiography. ARC biopsies were analyzed for Agrp mRNA via qPCR and for CREB and ERK proteins using capillary electrophoresis-based Western. HFD increased caloric uptake, leading to increases in body and fat mass (p<0.05). HFD had no effect on BP (24h MAP: chow 110±2 vs HFD 103±9 mmHg, n=8 each), but heart rate (HR; 555±12 vs 601±3 bpm, p<0.05) and HR variability (low/high freq. ratio: 0.6±0.08 vs 0.8±0.09, p<0.05) were increased by HFD, consistent with increased cardiac SNA. Stroke volume (41±2 vs 18±3 uL, n=10 each, p<0.05) and thus cardiac output (13±0.9 vs 6±1 mL/min, p<0.05) were significantly reduced with HFD, explaining normal BP despite increased cardiovascular SNA. HFD increased plasma leptin (p<0.05), decreased CREB (pCREB/CREB ratio: 0.7±0.1 n=4, vs 0.4±0.1, n=5, p<0.05) but increased ERK (pERK/ERK ratio: 8.4±1.2 vs 12.5±1.1, p<0.05) phosphorylation, and failed to suppress Agrp mRNA in the ARC. We conclude that prolonged HFD increases cardiovascular SNA in C57BL/6J mice without effect on BP because of cardiac compensation. Further, this model causes SLR at the level of the ARC Agrp neuron, in a mechanism likely involving alterations in CREB- and ERK-mediated signaling.

Single-Nucleus RNA Sequencing of the Hypothalamic Arcuate Nucleus of C57BL/6J Mice After Prolonged Diet-Induced Obesity.

Prolonged obesity is associated with blunted feeding and thermogenic autonomic responses to leptin, but cardiovascular responses to leptin are maintained. This state of selective leptin resistance is, therefore, proposed to contribute to the pathogenesis and maintenance of obesity-associated hypertension. Cells of the arcuate nucleus of the hypothalamus detect leptin, and although the cellular and molecular mechanisms remain unclear, altered arcuate nucleus biology is hypothesized to contribute to selective leptin resistance. Male C57BL/6J mice were fed a high-fat diet (HFD) or chow from 8 to 18 weeks of age, as this paradigm models selective leptin resistance. Nuclei were then isolated from arcuate nucleus for single-nucleus RNA sequencing. HFD caused expected gains in adiposity and circulating leptin. Twenty-three unique cell-type clusters were identified, and Ingenuity Pathway Analysis was used to explore changes in gene expression patterns due to chronic HFD within each cluster. Notably, gene expression signatures related to leptin signaling exhibited suppression predominantly in neurons identified as the Agouti-related peptide (Agrp) subtype. Ingenuity Pathway Analysis results were also consistent with alterations in CREB (cAMP response element-binding protein) signaling in Agrp neurons after HFD, and reduced phosphorylated CREB was confirmed in arcuate nucleus after prolonged HFD by capillary electrophoresis-based Western blotting. These findings support the concept that prolonged HFD-induced obesity is associated with selective changes in Agrp neuron biology, possibly secondary to altered CREB signaling.

Reversal of prolonged obesity-associated cerebrovascular dysfunction by inhibiting microglial Tak1.

Prolonged obesity is associated with cerebrovascular dysfunction; however, the underlying mechanisms remain largely unclear. In the present study, using a prolonged obesity mouse model that suffers from basilar artery (BA) abnormalities, we find that microglial transforming growth factor β-activated kinase 1 (Tak1) is over-activated in the brainstem. Both pharmacological inhibition primarily in the brainstem and genetic microglia-selective deletion of Tak1 ameliorated BA vascular dysfunction. Conversely, microglia-specific activation of Tak1 in the brainstem was sufficient to cause an impairment in BA function in chow-fed mice. Mechanistically, Tak1 activation leads to increased interleukin-18 (IL-18) production, whereas blockade of IL-18 receptor in the brain helped protect against cerebrovascular dysfunction despite prolonged obesity. Microglia-selective deletion of Tak1 also protects against ischemic stroke in prolonged obesity. Taken together, these findings provide evidence that microglial Tak1 in the brain, and particularly the brainstem, contributes to the pathogenesis of obesity-associated cerebrovascular dysfunction.

CREB and ERK Activation by Leptin and Angiotensin in the GT1‐7 Cell Model by Capillary Electrophoresis‐Based Western Blotting

Leptin (LEP) increases resting energy expenditure in part by decreasing Agouti‐related peptide (Agrp) within the arcuate nucleus (ARC) of the hypothalamus. Prolonged obesity is associated with hyperleptinemia and development of selective LEP resistance (SLR), referring to the loss of ‘metabolic’ but maintenance of ‘cardiovascular’ sympathetic nervous activity responses to LEP. Previously, we discovered that angiotensin II (ANG) type 1a (Agtr1a) receptors located on Agrp neurons of the ARC are dispensable for blood pressure control but critically required for metabolic responses to LEP. Therefore, we generally hypothesize a role for Agtr1a in Agrp neurons of the ARC in the development of SLR. We used single‐nucleus RNA‐seq followed by Ingenuity Pathway Analysis (IPA) to interrogate the transcriptomes of individual cell types of the ARC from mice after 10 weeks of 45% high fat diet (HFD) or chow. We determined that canonical LEP signaling was strongly under‐represented in Agrp neurons, but not other cell types. Similarly, CREB & ERK pathways, which are implicated in the control of Agrp expression, were significantly under‐represented within Agrp neurons from HFD‐fed mice. To explore changes in the function of these second‐messenger cascades in Agrp neurons, immortalized mouse hypothalamic GT1‐7 cells were examined for expression of relevant genes and activation of signaling cascades in response to various stimuli. First, GT1‐7 cells were confirmed to express Agrp, Lepr, and Agtr1a, but not proopiomelanocortin by qPCR. Second, GT1‐7 cells were treated with LEP (1uM), ANG (200nM), forskolin (30uM), or vehicle for 15 min and lysates were isolated for Western blotting. Capillary electrophoresis methodology (Protein Simple WES; standard matrix (12–230 kDa)/anti‐rabbit detection module) was specifically chosen to enable future studies of ARC Agrp neurons captured after dietary interventions by laser capture microdissection (LCM). Phosphorylated (p) CREB (1:50; CST # 9198), total (t) CREB (1:50; CST #9197), p‐ERK (10ug/ml; R&D Systems # AF1018‐SP), t‐ERK (10ug/ml; R&D Systems # AF1576‐SP) and β‐actin (1:100; Abcam ab8227) protein levels were assessed for all four treatments. Peak signal‐to‐noise (S/N) ratios were well above the threshold value of 10 for all protein samples: p‐CREB (ranging from 560–1500), t‐CREB (25–40), p‐ERK (115–1245) t‐ERK (150–270) and β‐actin (1400–1600). LEP, ANG, and forskolin treatment significantly (p<0.05; n=5–6 each) increased p‐CREB and p‐ERK with no change in t‐CREB or t‐ERK, compared to vehicle. Finally, the viability of protein collection from the ARC was confirmed and optimized by measuring β‐actin from cells isolated by LCM. Ongoing studies are focused on assessing ARC Agrp neuron CREB & ERK responses to acute leptin treatment after prolonged exposure to HFD.Support or Funding InformationHL134850, HL084207

Pregnancy and labor management: women with venous thromboembolism or associated significant risk factors

This paper describes diagnosis, treatment, and control of acute venous thromboembolism (VTE) and antithrombotic prophylactic management during pregnancy and puerperium, especially in women with inherited thrombophilia. VTE is currently one of the three main causes of maternal morbidity in Japan. With approximately 0.05%-0.08% incidence rate per total number of births, it is becoming increasingly comparable with other developed countries. Pregnancy is characterized by high blood clotting potential due to increased coagulation factors, decreased anticoagulant activity, and fibrinolysis. Additionally, unique obstetric risk factors exist, such as cesarean section, prolonged bed rest, obesity, preeclampsia, and dehydration due to hyperemesis. Moreover, notable risk factors for VTE in pregnancy and puerperium for patients with inherited thrombophilia (e.g., deficiencies in antithrombin, protein C, and protein S) and acquired thrombophilia (e.g., antiphospholipid antibodies, history of VTE) have been reported; this study describes inherited thrombophilia in details.

Portomesenteric Venous Thrombosis as a Complication of Laparoscopic Sleeve Gastrectomy: a Case Report and Review of the Literature

Portomesenteric venous thrombosis (PMVT) is a rare and potentially life-threatening condition with high morbidity and mortality. Its incidence is low as complication of bariatric surgery and laparoscopic sleeve gastrectomy (LSG) and the reason is unclear and is likely multifactorial. Genetic predisposition, oral contraceptive, thrombophilia, intra-abdominal pressure due to pneumoperitoneum, reverse Trendelenburg position, prolonged operation time, DM, and obesity may be considered as risk factors. Extended low-molecular-weight heparin anticoagulation prophylaxis to prevent PMVT is a reasonable choice for patients after LSG; however, no clear guidelines about the optimal dose, duration, and type of heparin are currently available. In this study, we present a case of a 50-year-old woman who was admitted to the emergency department for abdominal pain 2 weeks after LSG. Her computed tomography scan showed a portomesenteric venous thrombosis. Our review of the English literature found only 137 morbidly obese patients who had developed PMVT after bariatric surgery between 2002 and July 2018, demonstrating rarity of this complication.

2036-P: Gut Microbes Regulate Insulin Clearance in Mice

Obesity and insulin resistance are associated with hyperinsulinemia, which is caused by increased insulin secretion and/or reduced insulin clearance. Impaired insulin clearance may be caused by ectopic lipid deposition in liver and skeletal muscle, the key sites of insulin clearance and degradation. Insulin is the key hormone regulating blood glucose. The composition of the intestinal microbiota can regulate aspects of diet-induced obesity and glucose metabolism. Here we found that the microbiota also regulates insulin clearance during prolonged diet-induced obesity. Male C57Bl/6J mice fed 45% high fat diet (HFD) for a prolonged period had impaired insulin clearance relative to chow fed mice as measured by insulin/C-peptide ratio during an oral glucose tolerance test. High fat fed mice also showed impaired insulin clearance measured after injection of insulin - mice fed chow or 45% HFD had plasma insulin concentration measured at 0, 5, 30, and 60 minutes following injection of human insulin and area under the curve calculated. Treatment of 45% HFD-fed mice with an antibiotic cocktail of Neomycin/Ampicillin for 2 weeks improved insulin clearance after insulin injection. Next, we colonized previously germ-free mice with the microbiota from chow or 45% HFD-fed “donor” mice for 6 weeks. The previously germ-free “recipient” mice colonized with feces-resident microbes from chow or HFD fed donors did not differ in insulin clearance when recipient mice were fed a chow diet. However, when colonized recipient mice were switched from chow to 45% HFD for 2 weeks the recipient mice colonized with microbes from 45% HFD fed donors showed impaired insulin clearance relative to recipient mice colonized with microbes from chow fed donors. Our results demonstrate that diet-induced changes in fecal microbes are an independent factor regulating insulin clearance. Diet-induced changes in the gut microbiota and consequent impaired insulin clearance may participate in hyperinsulinemia leading to exacerbated insulin resistance and obesity. Disclosure K.P. Foley: None. S. Zlitni: None. B.M. Duggan: None. B.D. Henriksbo: None. N.G. Barra: None. J.F. Cavallari: None. F. Forato Anhê: None. T. Lau: None. Y. Chen: None. J.D. Schertzer: None. Funding Canadian Institutes of Health Research

Obesity, kidney dysfunction and hypertension: mechanistic links.

Excessive adiposity raises blood pressure and accounts for 65-75% of primary hypertension, which is a major driver of cardiovascular and kidney diseases. In obesity, abnormal kidney function and associated increases in tubular sodium reabsorption initiate hypertension, which is often mild before the development of target organ injury. Factors that contribute to increased sodium reabsorption in obesity include kidney compression by visceral, perirenal andrenal sinus fat; increased renal sympathetic nerve activity (RSNA); increased levels of anti-natriuretic hormones, such as angiotensin II and aldosterone; and adipokines, particularly leptin. The renal and neurohormonal pathways of obesity and hypertension are intertwined. For example, leptin increases RSNA by stimulating the central nervous system proopiomelanocortin-melanocortin 4 receptor pathway, and kidney compression and RSNA contribute to renin-angiotensin-aldosterone system activation. Glucocorticoids and/or oxidative stress may also contribute to mineralocorticoid receptor activation in obesity. Prolonged obesity and progressive renal injury often lead to the development of treatment-resistant hypertension. Patient management therefore often requires multiple antihypertensive drugs and concurrent treatment of dyslipidaemia, insulin resistance, diabetes and inflammation. If more effective strategies for the prevention and control of obesity are not developed, cardiorenal, metabolic and other obesity-associated diseases could overwhelm health-care systems in the future.

Long term but not short term exposure to obesity related microbiota promotes host insulin resistance

The intestinal microbiota and insulin sensitivity are rapidly altered after ingestion of obesogenic diets. We find that changes in the composition of the fecal microbiota precede changes in glucose tolerance when mice are fed obesogenic, low fiber, high fat diets (HFDs). Antibiotics alter glycemia during the first week of certain HFDs, but antibiotics show a more robust improvement in glycemic control in mice with protracted obesity caused by long-term feeding of multiple HFDs. Microbiota transmissible dysglycemia and glucose intolerance only occur when germ-free mice are exposed to obesity-related microbes for more than 45 days. We find that sufficient host exposure time to microbiota derived from HFD-fed mice allows microbial factors to contribute to insulin resistance, independently from increased adiposity in mice. Our results are consistent with intestinal microbiota contributing to chronic insulin resistance and dysglycemia during prolonged obesity, despite rapid diet-induced changes in the taxonomic composition of the fecal microbiota.

MORPHOLOGICAL CHANGES IN THE HEART WITH OBESITY

Obesity is often an additional and leading risk factor for arterial hypertension. The likelihood of hypertension development in individuals with obesity is 50% higher than that of people with normal body weight. Obesity provokes acceleration of the development of factors that make up the cardiovascular risk in general. In obese individuals, arterial hypertension is found 2.9 times more often than in people with normal body mass. In 80% of men and 61% of women included in the Framingham study, the cause of arterial hypertension was an increase in body weight. WHO experts draw the conclusion that in Western countries 1/3 of patients, on average, suffer from arterial hypertension due to excessive body weight, and in men up to 45 years this figure reaches 60%. Obesity and arterial hypertension potentiate each other in relation to the development of unfavorable effects on the structure and function of the heart; the level of pre- and after-load of the heart increases, especially in people with severe and prolonged (> 15 years) obesity. The risk of left ventricular myocardial hypertrophy (LVMH) formation rises from 5.5% in people with normal body weight up to 29.9% in obese people. Hypertension, when associated with obesity, increases the risk of heart hypertrophy more than 4 times. The problem of overweight is the scourge of our time. Obesity is diagnosed quite often. Therefore, a conservative approach is not always reasonable. Surgical treatments for obesity are rather relevant in turn. Objective: to establish morphological changes in the heart and vessels of the anterior abdominal wall and the small intestinal mucus in case of obesity and to establish their role in the occurrence of arterial hypertension. Materials and methods: obesity was modeled according to the standard method of high-calorie nutrition for a month. The weight of rats was 390-420 g. Results and Discussion: the changes in the heart and blood vessels in different areas developed as a result of obesity were examined. The samples of the heart walls are presented in all the layers – the epicardium, myocardium, and endocardium. The endocardium is of usual histological structure, represented by endothelial lining in the form of single layer flat epithelium and such underlying layers – loose connective tissue, muscular and elastic layer, and external connective tissue layer. On the longitudinal sections, cardiomyocytes are represented by cells of elongated rectangular shape with eosinophilic cytoplasm, rounded or oval nuclei, located centrally and paracentrally. The layers of loose connective tissue and vessels are located between the muscular elements of the myocardium. Diffusely located small eosinophilic grains in the cytoplasm of separate groups of cardiomyocytes are present (phenomena of granular myocardial dystrophy). The interstitial stroma is in moderate edema. The plethora of all the vessels of the myocardium (arteries, veins, microvasculature) is noticed and accompanied by erythrostasis phenomena; individual red blood cells are destroyed with the release of brown pigment in the lumen of the vessel. The walls of the vessels are swelled in some places, and the release of red blood cells from the vascular bed is marked around some of them. The anterior abdominal wall is represented by epidermis, dermis, underlying fatty tissue, and muscle layer. In the lumen of the vessels erythrostasis is manifested significantly. The mesentery is represented by the adipose tissue of a usual histological structure with regional lymph nodes. Vessels are full-blooded, in some places defibration and swelling of the muscular layer are present. Conclusions: As it is evident from the histological sections, the reaction of all the parts of the cardiovascular system is expressed in pathological changes that subsequently lead to arterial hypertension and cardiovascular insufficiency.

Nutrition versus Functional Respiratory Capacity: A Cardinal Interplay

Right from the very beginning of life on earth, organisms have always been in search for sources of energy. From the most primitive of organisms to where biodiversity stands today, the demand of energy has always been met by the supply of food. Nutrition plays a crucial role in normal functioning of all the organs of our body. Any form of imbalance in the dietary intake becomes evident in the concerned physiology. This study was undertaken to explore the variations of Functional Respiratory Capacities (FRCs) associated with diet and the underpinned lifestyle habits in a sample of 70 (36 male/34 female) college going students in Delhi within the age group of 19–21.Balanced diet is a pre‐requisite for a healthy lifestyle. But one of the major problems faced by developing countries is malnourishment, wherein the nutrient intake is either insufficient or over‐sufficient. As dyspnea and poor lung volumes are theoretically expected in people with the global phenomenon of obesity, this study aimed at correlating the data of three major functional respiratory parameters, Forced Vital Capacity (FVC), Forced Expiratory Volume in the first second of expiration (FEV) and FEV % {(FEV /FVC) × 100} obtained using a MiniSpir spirometer and the answers in the questionnaire concerning dietary and lifestyle habits filled by the volunteers themselves. An additional insight into the analysis was made by calculating the Body Mass Index (BMI) of the volunteers using a Tanita InnerScanV Body Composition Analyser.The pulmonary function results obtained was typically a spectrum of restrictions and obstructions flanked by normal spirometry. Volunteers who indulged themselves in cigarettes and alcohol showed mild to severe obstructions, and those feeding on excessive calories showed mild to severe restrictions. High calorie intake (prolonged obesity) and cigarette smoking could increase the severity of the results (which were mild given the age group of volunteers) in due course of time, possibly deteriorating their pulmonary health further down the line.Support or Funding InformationResearch Council, University of Delhi

High-fat diet induced obesity primes inflammation in adipose tissue prior to liver in C57BL/6j mice.

Metabolic inflammation in adipose tissue and the liver is frequently observed as a result of diet-induced obesity in human and rodent studies. Although the adipose tissue and the liver are both prone to become chronically inflamed with prolonged obesity, their individual contribution to the development of metabolic inflammation remains speculative. Thus, we aimed to elucidate the sequence of inflammatory events in adipose and hepatic tissues to determine their contribution to the development of metabolic inflammation and insulin resistance (IR) in diet-induced obesity. To confirm our hypothesis that adipose tissue (AT) inflammation is initiated prior to hepatic inflammation, C57BL/6J male mice were fed a low-fat diet (LFD; 10% kcal fat) or high-fat diet (HFD; 45% kcal fat) for either 24, 40 or 52 weeks. Lipid accumulation and inflammation was measured in AT and liver. Glucose tolerance was assessed and plasma levels of glucose, insulin, leptin and adiponectin were measured at various time points throughout the study. With HFD, C57BL/6j mice developed a progressive obese phenotype, accompanied by IR at 24 and 40 weeks of HFD, but IR was attenuated after 52 weeks of HFD. AT inflammation was present after 24 weeks of HFD, as indicated by the increased presence of crown-like structures and up-regulation of pro-inflammatory genes Tnf, Il1β, Mcp1 and F4/80. As hepatic inflammation was not detected until 40 weeks of HFD, we show that AT inflammation is established prior to the development of hepatic inflammation. Thus, AT inflammation is likely to have a greater contribution to the development of IR compared to hepatic inflammation.