Brown adipose tissue metabolism in women is dependent on ovarian status.

In rodents, loss of estradiol (E2) reduces brown adipose tissue (BAT) metabolic activity. Whether E2 impacts BAT activity in women is not known. BAT oxidative metabolism was measured in premenopausal (n = 27; 35 ± 9 yr; body mass index = 26.0 ± 5.3 kg/m2) and postmenopausal (n = 25; 51 ± 8 yr; body mass index = 28.0 ± 5.0 kg/m2) women at room temperature and during acute cold exposure using [11C]acetate with positron emission tomography coupled with computed tomograph. BAT glucose uptake was also measured during acute cold exposure using 2-deoxy-2-[18F]fluoro-d-glucose. To isolate the effects of ovarian hormones from biological aging, measurements were repeated in a subset of premenopausal women (n = 8; 40 ± 4 yr; BMI = 28.0 ± 7.2 kg/m2) after 6 mo of gonadotropin-releasing hormone agonist therapy to suppress ovarian hormones. At room temperature, there was no difference in BAT oxidative metabolism between premenopausal (0.56 ± 0.31 min-1) and postmenopausal women (0.63 ± 0.28 min-1). During cold exposure, BAT oxidative metabolism (1.28 ± 0.85 vs. 0.91 ± 0.63 min-1, P = 0.03) and net BAT glucose uptake (84.4 ± 82.5 vs. 29.7 ± 31.4 nmol·g-1·min-1, P < 0.01) were higher in premenopausal than postmenopausal women. In premenopausal women who underwent gonadotropin-releasing hormone agonist, cold-stimulated BAT oxidative metabolism was reduced to a similar level (from 1.36 ± 0.66 min-1 to 0.91 ± 0.41 min-1) to that observed in postmenopausal women (0.91 ± 0.63 min-1). These results provide the first evidence in humans that reproductive hormones are associated with BAT oxidative metabolism and suggest that BAT may be a target to attenuate age-related reduction in energy expenditure and maintain metabolic health in postmenopausal women.NEW & NOTEWORTHY In rodents, loss of estrogen reduces brown adipose tissue (BAT) activity. Whether this is true in humans is not known. We found that BAT oxidative metabolism and glucose uptake were lower in postmenopausal compared to premenopausal women. In premenopausal women who underwent ovarian suppression to reduce circulating estrogen, BAT oxidative metabolism was reduced to postmenopausal levels. Thus the loss of ovarian function in women leads to a reduction in BAT metabolic activity independent of age.

Altered branched-chain α-keto acid metabolism is a feature of NAFLD in individuals with severe obesity.

Hepatic de novo lipogenesis is influenced by the branched-chain α-keto acid dehydrogenase (BCKDH) kinase (BCKDK). Here, we aimed to determine whether circulating levels of the immediate substrates of BCKDH, the branched-chain α-keto acids (BCKAs), and hepatic BCKDK expression are associated with the presence and severity of nonalcoholic fatty liver disease (NAFLD). Eighty metabolites (3 BCKAs, 14 amino acids, 43 acylcarnitines, 20 ceramides) were quantified in plasma from 288 patients with bariatric surgery with severe obesity and scored liver biopsy samples. Metabolite principal component analysis factors, BCKAs, branched-chain amino acids (BCAAs), and the BCKA/BCAA ratio were tested for associations with steatosis grade and presence of nonalcoholic steatohepatitis (NASH). Of all analytes tested, only the Val-derived BCKA, α-keto-isovalerate, and the BCKA/BCAA ratio were associated with both steatosis grade and NASH. Gene expression analysis in liver samples from 2 independent bariatric surgery cohorts showed that hepatic BCKDK mRNA expression correlates with steatosis, ballooning, and levels of the lipogenic transcription factor SREBP1. Experiments in AML12 hepatocytes showed that SREBP1 inhibition lowered BCKDK mRNA expression. These findings demonstrate that higher plasma levels of BCKA and hepatic expression of BCKDK are features of human NAFLD/NASH and identify SREBP1 as a transcriptional regulator of BCKDK.

The transcription factor hepatocyte nuclear factor 4A acts in the intestine to promote white adipose tissue energy storage.

The transcription factor hepatocyte nuclear factor 4 A (HNF4A) controls the metabolic features of several endodermal epithelia. Both HNF4A and HNF4G are redundant in the intestine and it remains unclear whether HNF4A alone controls intestinal lipid metabolism. Here we show that intestinal HNF4A is not required for intestinal lipid metabolism per se, but unexpectedly influences whole-body energy expenditure in diet-induced obesity (DIO). Deletion of intestinal HNF4A caused mice to become DIO-resistant with a preference for fat as an energy substrate and energetic changes in association with white adipose tissue (WAT) beiging. Intestinal HNF4A is crucial for the fat-induced release of glucose-dependent insulinotropic polypeptide (GIP), while the reintroduction of a stabilized GIP analog rescues the DIO resistance phenotype of the mutant mice. Our study provides evidence that intestinal HNF4A plays a non-redundant role in whole-body lipid homeostasis and points to a non-cell-autonomous regulatory circuit for body-fat management.

IGFBP-2 partly mediates the early metabolic improvements caused by bariatric surgery.

Insulin-like growth factor-binding protein (IGFBP)-2 is a circulating biomarker of cardiometabolic health. Here, we report that circulating IGFBP-2 concentrations robustly increase after different bariatric procedures in humans, reaching higher levels after biliopancreatic diversion with duodenal switch (BPD-DS) than after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). This increase is closely associated with insulin sensitization. In mice and rats, BPD-DS and RYGB operations also increase circulating IGFBP-2 levels, which are not affected by SG or caloric restriction. In mice, Igfbp2 deficiency significantly impairs surgery-induced loss in adiposity and early improvement in insulin sensitivity but does not affect long-term enhancement in glucose homeostasis. This study demonstrates that the modulation of circulating IGFBP-2 may play a role in the early improvement of insulin sensitivity and loss of adiposity brought about by bariatric surgery.

Association between changes in bioactive osteocalcin and glucose homeostasis after biliopancreatic diversion.

PURPOSE: Bone may regulate glucose homeostasis via uncarboxylated bioactive osteocalcin (ucOCN). This study explored whether changes in ucOCN and bone remodeling are associated with change in glucose homeostasis after biliopancreatic diversion (BPD). METHODS: In this secondary exploratory analysis of a 1-year prospective observational study, 16 participants (11 men/5 women; 69% with type 2 diabetes; mean BMI 49.4 kg/m2) were assessed before, 3 days, 3 months and 12 months after BPD. Changes in plasma ucOCN and bone markers (C-terminal telopeptide (CTX), total osteocalcin (OCN)) were correlated with changes in insulin resistance or sensitivity indices (HOMA-IR; adipose tissue insulin resistance index (ADIPO-IR) and insulin sensitivity index (SI) from the hyperinsulinemic-euglycemic clamp), insulin secretion rate (ISR) from the hyperglycemic clamp, and disposition index (DI: SI × ISR) using Spearman correlations before and after adjustment for weight loss. RESULTS: ucOCN was unchanged at 3 days but increased dramatically at 3 months (+257%) and 12 months (+498%). Change in ucOCN correlated significantly with change in CTX at 3 months (r = 0.62, p = 0.015) and 12 months (r = 0.64, p = 0.025) before adjustment for weight loss. It also correlated significantly with change in fasting insulin (r = -0.53, p = 0.035), HOMA-IR (r = -0.54, p = 0.033) and SI (r = 0.52, p = 0.041) at 3 days, and ADIPO-IR (r = -0.69, p = 0.003) and HbA1c (r = -0.69, p = 0.005) at 3 months. Change in OCN did not correlate with any glucose homeostasis indices. Results were similar after adjustment for weight loss. CONCLUSION: The increase in ucOCN may be associated with the improvement in insulin resistance after BPD, independently of weight loss. These findings need to be confirmed in larger, less heterogeneous populations.

Seven-day overfeeding enhances adipose tissue dietary fatty acid storage and decreases myocardial and skeletal muscle dietary fatty acid partitioning in healthy subjects.

Increased myocardial partitioning of dietary fatty acids (DFA) and decreased left ventricular (LV) function is associated with insulin resistance in prediabetes. We hypothesized that enhanced myocardial DFA partitioning and reduced LV function might be induced concomitantly with reduced insulin sensitivity upon a 7-day hypercaloric (+50% in caloric intake), high-saturated fat (~11%energy), and simple carbohydrates (~54%energy) diet (HIGHCAL) versus an isocaloric diet (ISOCAL) with a moderate amount of saturated fat (~8%energy) and carbohydrates (~50%energy). Thirteen healthy subjects (7 men/6 women) underwent HIGHCAL versus ISOCAL in a randomized crossover design, with organ-specific DFA partitioning and LV function measured using the oral 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid and [11C]acetate positron emission tomography methods at the end of both interventions. HIGHCAL induced a decrease in insulin sensitivity indexes with no significant change in body composition. HIGHCAL led to increased subcutaneous abdominal (+4.2 ± 1.6%, P < 0.04) and thigh (+2.4 ± 1.2%, P < 0.08) adipose tissue storage and reduced cardiac (-0.31 ± 0.11 mean standard uptake value [(SUV), P < 0.03] and skeletal muscle (-0.17 ± 0.08 SUV, P < 0.05) DFA partitioning without change in LV function. We conclude that early increase in adipose tissue DFA storage protects the heart and skeletal muscles from potential deleterious effects of DFA.

Bariatric Surgery Rapidly Decreases Cardiac Dietary Fatty Acid Partitioning and Hepatic Insulin Resistance Through Increased Intra-abdominal Adipose Tissue Storage and Reduced Spillover in Type 2 Diabetes.

Reduced storage of dietary fatty acids (DFAs) in abdominal adipose tissues with enhanced cardiac partitioning has been shown in subjects with type 2 diabetes (T2D) and prediabetes. We measured DFA metabolism and organ partitioning using positron emission tomography with oral and intravenous long-chain fatty acid and glucose tracers during a standard liquid meal in 12 obese subjects with T2D before and 8-12 days after bariatric surgery (sleeve gastrectomy or sleeve gastrectomy and biliopancreatic diversion with duodenal switch). Bariatric surgery reduced cardiac DFA uptake from a median (standard uptake value [SUV]) 1.75 (interquartile range 1.39-2.57) before to 1.09 (1.04-1.53) after surgery (P = 0.01) and systemic DFA spillover from 56.7 mmol before to 24.7 mmol over 6 h after meal intake after surgery (P = 0.01), with a significant increase in intra-abdominal adipose tissue DFA uptake from 0.15 (0.04-0.31] before to 0.49 (0.20-0.59) SUV after surgery (P = 0.008). Hepatic insulin resistance was significantly reduced in close association with increased DFA storage in intra-abdominal adipose tissues (r = -0.79, P = 0.05) and reduced DFA spillover (r = 0.76, P = 0.01). We conclude that bariatric surgery in subjects with T2D rapidly reduces cardiac DFA partitioning and hepatic insulin resistance at least in part through increased intra-abdominal DFA storage and reduced spillover.

Specific loss of adipocyte CD248 improves metabolic health via reduced white adipose tissue hypoxia, fibrosis and inflammation.

BACKGROUND: A positive energy balance promotes white adipose tissue (WAT) expansion which is characterized by activation of a repertoire of events including hypoxia, inflammation and extracellular matrix remodelling. The transmembrane glycoprotein CD248 has been implicated in all these processes in different malignant and inflammatory diseases but its potential impact in WAT and metabolic disease has not been explored. METHODS: The role of CD248 in adipocyte function and glucose metabolism was evaluated by omics analyses in human WAT, gene knockdowns in human in vitro differentiated adipocytes and by adipocyte-specific and inducible Cd248 gene knockout studies in mice. FINDINGS: CD248 is upregulated in white but not brown adipose tissue of obese and insulin-resistant individuals. Gene ontology analyses showed that CD248 expression associated positively with pro-inflammatory/pro-fibrotic pathways. By combining data from several human cohorts with gene knockdown experiments in human adipocytes, our results indicate that CD248 acts as a microenvironmental sensor which mediates part of the adipose tissue response to hypoxia and is specifically perturbed in white adipocytes in the obese state. Adipocyte-specific and inducible Cd248 knockouts in mice, both before and after diet-induced obesity and insulin resistance/glucose intolerance, resulted in increased microvascular density as well as attenuated hypoxia, inflammation and fibrosis without affecting fat cell volume. This was accompanied by significant improvements in insulin sensitivity and glucose tolerance. INTERPRETATION: CD248 exerts detrimental effects on WAT phenotype and systemic glucose homeostasis which may be reversed by suppression of adipocyte CD248. Therefore, CD248 may constitute a target to treat obesity-associated co-morbidities.

Determination of a pharmacokinetic model for [11C]-acetate in brown adipose tissue.

BACKGROUND: [11C]-acetate positron emission tomography is used to assess oxidative metabolism in various tissues including the heart, tumor, and brown adipose tissue. For brown adipose tissue, a monoexponential decay model is commonly employed. However, no systematic assessment of kinetic models has been performed to validate this model or others. The monoexponential decay model and various compartmental models were applied to data obtained before and during brown adipose tissue activation by cold exposure in healthy men. Quality of fit was assessed visually and by analysis of residuals, including the Akaike information criterion. Stability and accuracy of compartmental models were further assessed through simulations, along with sensitivity and identifiability of kinetic parameters. RESULTS: Differences were noted in the arterial input function between the warm and cold conditions. These differences are not taken into account by the monoexponential decay model. They are accounted for by compartmental models, but most models proved too complex to be stable. Two and three-tissue models with no more than four distinct kinetic parameters, including blood volume fraction, provided the best compromise between fit quality and stability/accuracy. CONCLUSION: For healthy men, a three-tissue model with four kinetic parameters, similar to a heart [11C]-palmitate model seems the most appropriate based on model stability and its ability to describe the main [11C]-acetate pathways in BAT cells. Further studies are required to validate this model in women and people with metabolic disorders.

Acute and chronic effect of bariatric surgery on circulating autotaxin levels.

Autotaxin (ATX), an adipose tissue-derived lysophospholipase, has been involved in the pathophysiology of cardiometabolic diseases. The impact of bariatric surgery on circulating ATX levels is unknown. We examined the short- (24 h, 5 days) and longer-term (6 and 12 months) impact of bariatric surgery; as well as the short-term effect of caloric restriction (CR) on plasma ATX levels in patients with severe obesity. We measured ATX levels in 69 men and women (mean age: 41 ± 11 years, body mass index: 49.8 ± 7.1 kg/m2 ), before and after biliopancreatic diversion with duodenal switch surgery (BPD-DS) as well as in a control group (patients with severe obesity without surgery; n = 34). We also measured ATX levels in seven patients with severe obesity and type 2 diabetes who underwent a 3-day CR protocol before their BPD-DS. At baseline, ATX levels were positively associated with body mass index, fat mass, insulin resistance (HOMA-IR) as well as insulin and leptin levels and negatively with fat-free mass. ATX concentrations decreased 26.2% at 24 h after BPD-DS (342.9 ± 152.3 pg/mL to 253.2 ± 68.9 pg/mL, P < 0.0001) and by 16.4% at 12 months after BPD-DS (342.9 ± 152.3 pg/mL to 286.8 ± 182.6 pg/mL, P = 0.04). ATX concentrations were unchanged during follow-up in the control group (P = 0.4), and not influenced by short-term CR. In patients with severe obesity, bariatric surgery induced a rapid and sustained decrease in plasma ATX levels. Acute changes in ATX may not be explained by bariatric surgery-induced CR.

HNF4α is a novel regulator of intestinal glucose-dependent insulinotropic polypeptide.

Mutations in the HNF4A gene cause MODY1 and are associated with an increased risk of Type 2 diabetes mellitus. On the other hand, incretins are hormones that potentiate reductions in blood glucose levels. Given the established role of incretin-based therapy to treat diabetes and metabolic disorders, we investigated a possible regulatory link between intestinal epithelial HNF4α and glucose-dependent insulinotropic polypeptide (GIP), an incretin that is specifically produced by gut enteroendocrine cells. Conditional deletion of HNF4α in the whole intestinal epithelium was achieved by crossing Villin-Cre and Hnf4αloxP/loxP C57BL/6 mouse models. GIP expression was measured by qPCR, immunofluorescence and ELISA. Gene transcription was assessed by luciferase and electrophoretic mobility shift assays. Metabolic parameters were analyzed by indirect calorimetry and dual-energy X-ray absorptiometry. HNF4α specific deletion in the intestine led to a reduction in GIP. HNF4α was able to positively control Gip transcriptional activity in collaboration with GATA-4 transcription factor. Glucose homeostasis and glucose-stimulated insulin secretion remained unchanged in HNF4α deficient mice. Changes in GIP production in these mice did not impact nutrition or energy metabolism under normal physiology but led to a reduction of bone area and mineral content, a well described physiological consequence of GIP deficiency. Our findings point to a novel regulatory role between intestinal HNF4α and GIP with possible functional impact on bone density.

Effects of Biliopancreatic Diversion on Bone Turnover Markers and Association with Hormonal Factors in Patients with Severe Obesity.

BACKGROUND: This study evaluated early and medium-term changes in bone turnover markers, and their associations with weight loss, total bone mineral density (BMD), and hormonal changes after biliopancreatic diversion (BPD). METHODS: Ancillary study from a one-year prospective cohort of 16 individuals assessed before, 3 days, 3 and 12 months after BPD. Bone turnover markers (C-terminal telopeptide (CTX), intact osteocalcin (OC), sclerostin, and osteoprotegerin (OPG)) and several hormones were measured at each visit. Total BMD by DXA was assessed at baseline, 3 and 12 months after BPD. Three participants were lost to follow-up. RESULTS: CTX increased significantly at 3 days (+ 66%), 3 months (+ 219%), and 12 months (+ 295%). OC decreased at 3 days (- 19%) then increased at 3 months (+ 69%) and 12 months (+ 164%). Change in sclerostin was only significant between 3 days and 3 months (+ 13%), while change in OPG was significant between baseline and 3 days (+ 48%) and baseline and 12 months (+ 45%). CTX increase correlated negatively with weight loss at 3 (r = - 0.63, p = 0.009) and 12 months (r = - 0.58, p = 0.039), and total BMD decrease (r = - 0.67, p = 0.033) at 12 months. Change in insulin and adiponectin correlated with changes in bone turnover markers independently of weight loss. CONCLUSION: BPD causes an earlier and greater increase in bone resorption over bone formation markers and a decrease in total BMD. Sclerostin did not increase as expected following extensive weight loss. Changes in insulin and adiponectin seem to play a role in the activation of bone remodeling after BPD.

A Linear Fragment of Unacylated Ghrelin (UAG6-13) Protects Against Myocardial Ischemia/Reperfusion Injury in Mice in a Growth Hormone Secretagogue Receptor-Independent Manner.

Unacylated ghrelin (UAG), the most abundant form of ghrelin in circulation, has been shown to exert cardioprotective effect in experimental cardiopathies. The present study aimed to investigate the cardioprotective effect of a linear bioactive fragment of UAG against myocardial ischemia-induced injury and dysfunction in C57BL/6 wild type mice and the mechanisms involved. Treatments were administered at doses of 100 (UAG), 1,000 and 3,000 (UAG6-13) nmol/kg at 12 h interval during 14 days prior to 30 min left coronary artery ligation and reperfusion for a period of 6 or 48 h. The infarct area was decreased in a dose-dependent manner at 48 h of reperfusion, with a reduction of 54% at the highest dose of UAG6-13 tested. Myocardial hemodynamics were improved as demonstrated by an increase in cardiac output, maximum first derivative of left ventricular pressure, and preload recruitable stroke work, a load-independent contractility index. Six hours after reperfusion, circulating levels of IL-6 and TNF-α pro-inflammatory cytokines were reduced, and the effect was maintained at 48 h for TNF-α. 5' AMP-activated protein kinase (AMPK) was activated, while acetyl-CoA carboxylase (ACC) activity was inhibited, along with a decrease in apoptotic protein levels. In isolated hearts, the effect of UAG6-13 was unaffected by the presence of D-Lys3-GHRP-6, a ghrelin receptor (GHSR1a) antagonist, suggesting that the peptide acted through a GHSR1a-independent pathway. The results support the therapeutic application of UAG bioactive peptide fragments against myocardial ischemia/reperfusion injury.

Adiponectin has a pivotal role in the cardioprotective effect of CP-3(iv), a selective CD36 azapeptide ligand, after transient coronary artery occlusion in mice.

CD36 is a multiligand receptor involved in lipid metabolism. We investigated the mechanisms underlying the cardioprotective effect of CP-3(iv), an azapeptide belonging to a new class of selective CD36 ligands. The role of CP-3(iv) in mediating cardioprotection was investigated because CD36 signaling leads to activation of peroxisome proliferator-activated receptor-γ, a transcriptional regulator of adiponectin. CP-3(iv) pretreatment reduced infarct size by 54% and preserved hemodynamics in C57BL/6 mice subjected to 30 min coronary ligation and reperfusion but had no effect in CD36-deficient mice. The effects of CP-3(iv) were associated with an increase in circulating adiponectin levels, epididymal fat adiponectin gene expression, and adiponectin transcriptional regulators ( Pparg, Cebpb, Sirt1) after 6 h of reperfusion. Reduced myocardial oxidative stress and apoptosis were observed along with an increase in expression of myocardial adiponectin target proteins, including cyclooxygenase-2, phospho-AMPK, and phospho-Akt. Moreover, CP-3(iv) increased myocardial performance in isolated hearts, whereas blockade of adiponectin with an anti-adiponectin antibody abrogated it. CP-3(iv) exerts cardioprotection against myocardial ischemia and reperfusion (MI/R) injury and dysfunction, at least in part, by increasing circulating and myocardial adiponectin levels. Hence, both paracrine and endocrine effects of adiponectin may contribute to reduced reactive oxygen species generation and apoptosis after MI/R, in a CD36-dependent manner.-Huynh, D. N., Bessi, V. L., Ménard, L., Piquereau, J., Proulx, C., Febbraio, M., Lubell, W. D., Carpentier, A. C., Burelle, Y., Ong, H., Marleau, S. Adiponectin has a pivotal role in the cardioprotective effect of CP-3(iv), a selective CD36 azapeptide ligand, after transient coronary artery occlusion in mice.

Acute and Chronic Impact of Bariatric Surgery on Plasma LDL Cholesterol and PCSK9 Levels in Patients With Severe Obesity.

Context: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of low-density lipoprotein cholesterol (LDL-C) concentrations. In patients with severe obesity, biliopancreatic diversion with duodenal switch (BPD-DS) surgery induces substantial weight loss and influences lipoprotein metabolism. The effect of BPD-DS on PCSK9 levels is unknown. Objectives: To determine the acute and chronic impact of BPD-DS on PCSK9 levels and whether the acute impact of BPD-DS could be explained by BPD-DS-associated caloric restriction (CR). Design, Settings, and Participants: PCSK9 levels were measured in 20 men and 49 women (age, 41.5 ± 11.1 years) with severe obesity before, 24 hours, 5 days, and 6 and 12 months after BPD-DS and in a comparable control group (n = 31) at baseline and at 6 and 12 months. PCSK9 levels were also measured during 3-day CR in patients (n = 7) with severe obesity and type 2 diabetes. Results: PCSK9 levels increased 13.4% after 24 hours (248.7 ± 64.8 to 269.7 ± 63.8 ng/mL; P = 0,02) and decreased 9.5% at 12 months compared with baseline (217.6 ± 43.0 ng/mL; P < 0,0001). LDL-C levels decreased 36.2% after 24 hours (2.6 ± 0.7 to 1.7 ± 0.6 mmol/L; P < 0.0001) and 30% at 12 months compared with baseline (1.7 ± 0.5 mmol/L; P < 0.0001). Compared with baseline levels, PCSK9 levels were lower at day 2 but not at day 1 or 3 after CR. Conclusion: BPD-DS is associated with acute increases in PCSK9 levels that do not appear to be explained by CR but may be due to an acute response following surgery. BPD-DS induces chronic reductions in both PCSK9 and LDL-C levels.

Biliopancreatic diversion with duodenal switch leads to better postprandial glucose level and beta cell function than sleeve gastrectomy in individuals with type 2 diabetes very early after surgery.

OBJECTIVE: The aim of this study was to compare the short-term effect of sleeve gastrectomy (SG) and biliopancreatic diversion with duodenal switch (DS) in order to determine if exclusion of the upper gastrointestinal tract confers greater metabolic improvement, independent of weight loss. METHODS: Standard meals were administered before and on day 3 and 4 after SG to assess insulin sensitivity, ß-cell function and gastrointestinal hormone responses in matched normoglycemic (NG) and type 2 diabetes (T2D) participants. A third group of matched T2D participants who underwent DS with the same meal test administered prior to and 3days after surgery was also recruited. RESULTS: Despite significant metabolic improvement, T2D participants failed to fully normalize insulin resistance and ß-cell dysfunction 3 and 4days after SG. Our results demonstrate the superiority of DS over SG in terms of short-term improvement in postprandial glucose excursion and ß-cell function 3days after the surgery, with similar improvement in hepatic insulin sensitivity. CONCLUSION: Our findings support the notion that caloric restriction represents an important mechanism to explain the very early anti-diabetic effects observed after bariatric surgery. However, exclusion of the upper gastrointestinal tract also provides further metabolic improvements, possibly mediated by gastrointestinal hormonal responses and altered postprandial glucose absorption.

Fatty Acid Metabolic Remodeling During Type 2 Diabetes Remission After Bariatric Surgery.

Hypertrophic remodeling of white adipose tissues is associated with overexposure of lean organs to circulating triglycerides (TGs) and nonesterified fatty acids (NEFAs), ultimately leading to insulin resistance. Bariatric surgery promotes type 2 diabetes (T2D) remission through a succession of weight loss-dependent and -independent mechanisms. However, the longitudinal contribution of adipocyte size reduction and fatty acid metabolic handling remain unknown. Here we show that severely obese participants with T2D display hypertriglyceridemia and excessive systemic lipolysis during intravenous lipid overload. Three days after biliopancreatic diversion with duodenal switch (DS), whole-body glycerol turnover was normalized and associated with lower HOMA-insulin resistance index. A mean excess weight loss of 84% was achieved 12 months after DS. The smaller subcutaneous adipocyte size predicted better glycemic control in T2D. TG disposal and acylcarnitine production during lipid overload, along with muscle insulin sensitivity, improved with weight loss. Nevertheless, systemic NEFA fluxes and NEFA spillover remained similar, suggesting that increased NEFA storage capacity per volume of adipose tissue exactly compensated for the decrease in fat mass during weight loss. In conclusion, T2D remission after DS is mainly associated with greater circulating TG disposal, lower systemic lipolysis, and better fatty acid handling by lean tissues.

HNF1α defect influences post-prandial lipid regulation.

PURPOSE: Hepatocyte nuclear factor 1 alpha (HNF1α) defects cause Mature Onset Diabetes of the Young type 3 (MODY3), characterized by defects in beta-cell insulin secretion. However, HNF1α is involved in many other metabolic pathways with relevance for monogenic or polygenic type 2 diabetes. We aimed to investigate gut hormones, lipids, and insulin regulation in response to a meal test in HNF1α defect carriers (MODY3) compared to non-diabetic subjects (controls) and type 2 diabetes (T2D). METHODS: We administered a standardized liquid meal to each participant. Over 6 hours, we measured post-meal responses of insulin regulation (blood glucose, c-peptide, insulin), gut hormones (ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1) and lipids (non-esterified fatty acids [NEFA] and triglycerides). RESULTS: We found that MODY3 participants had lower insulin secretion indices than controls and T2D participants, showing the expected ß-cell defect. MODY3 had similar glycated hemoglobin levels (HbA1c median [IQR]: 6.5 [5.6-7.6]%) compared to T2D (median: 6.6 [6.2-6.9]%; P<0.05). MODY3 had greater insulin sensitivity (Matsuda index: 71.9 [29.6; 125.5]) than T2D (3.2 [4.0; 6.0]; P<0.05). MODY3 experienced a larger decrease in the ratio of NEFA to insulin (NEFA 30-0 / insulin 30-0: -39 [-78; -30] x104) in the early post-prandial period (0-30 minutes) compared to controls and to T2D (-2.0 [-0.6; -6.4] x104; P<0.05). MODY3 had lower fasting (0.66 [0.46; 1.2] mM) and post-meal triglycerides levels compared to T2D (fasting: 2.3 [1.7; 2.7] mM; P<0.05). We did not detect significant post-meal differences in ghrelin and incretins between MODY3 and other groups. CONCLUSION: In response to a standard meal test, MODY3 showed greater early post-prandial NEFA diminution in response to relatively low early insulin secretion, and they maintained very low post-prandial triglycerides levels.

Early Metabolic Improvement After Bariatric Surgery: The First Steps Toward Remission of Type 2 Diabetes.

The introduction of bariatric surgery into clinical practice in the 1980s was followed by a relatively long watch-and-wait period before the very rapid accumulation of scientific literature, over the past decade, concerning its clinical effectiveness and safety and its mechanisms of action in the treatment of obesity. These surgical procedures now emerge as the most effective therapeutic modality to induce long-term remission of type 2 diabetes. Recent research has shed light on the potential mechanisms leading to the profound improvement of glucose homeostasis following most bariatric surgery procedures. These mechanisms can be classified as weight loss dependent and independent, both playing sequential and then synergistic antidiabetes roles. Many groups, including our own, have contributed to our understanding of the relative roles of these mechanisms at differing time periods following these procedures. Here we summarize what we currently know about the mechanisms underlying the very rapid, weight loss-independent improvement in glucose homeostasis after bariatric surgery. Beyond its impact in the field of bariatric surgery, this new knowledge about the very rapid in vivo "reverse engineering" of type 2 diabetes actually provides unique insights into the intricate and complex mechanisms linking nutrition and obesity with the development of this disease.

[(11)C]-Acetoacetate PET imaging: a potential early marker for cardiac heart failure.

UNLABELLED: The ketone body acetoacetate could be used as an alternate nutrient for the heart, and it also has the potential to improve cardiac function in an ischemic-reperfusion model or reduce the mitochondrial production of oxidative stress involved in cardiotoxicity. In this study, [(11)C]-acetoacetate was investigated as an early marker of intracellular damage in heart failure. METHODS: A rat cardiotoxicity heart failure model was induced by doxorubicin, Dox(+). [(14)C]-Acetoacetate, a non-positron (ß-) emitting radiotracer, was used to characterize the arterial blood input function and myocardial mitochondrial uptake. Afterward, [(11)C]-acetoacetate (ß+) myocardial PET images were obtained for kinetic analysis and heart function assessment in control Dox(-) (n=15) and treated Dox(+) (n=6) rats. The uptake rate (K1) and myocardial clearance rate (k2or kmono) were extracted. RESULTS: [(14)C]-Acetoacetate in the blood was increased in Dox(+), from 2 min post-injection until the last withdrawal point when the heart was harvested, as well as the uptake in the heart and myocardial mitochondria (unpaired t-test, p <0.05). PET kinetic analysis of [(11)C]-acetoacetate showed that rate constants K1, k2 and kmono were decreased in Dox(+) (p <0.05) combined with a reduction of 24% of the left ventricular ejection fraction (p <0.001). CONCLUSION: Radioactive acetoacetate ex vivo analysis [(14)C], and in vivo kinetic [(11)C] studies provided evidence that [(11)C]-acetoacetate can assess heart failure Dox(+). Contrary to myocardial flow reserve (rest-stress protocol), [(11)C]-acetoacetate can be used to assess reduced kinetic rate constants without requirement of hyperemic stress response. The proposed [(11)C]-acetoacetate cardiac radiotracer in the investigation of heart disease is novel and paves the way to a potential role for [(11)C]-acetoacetate in cardiac pathophysiology.