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Obesity contributes to reduced life expectancy because of its link with type 2 diabetes and cardiovascular disease. Yet, targeting this poorly diagnosed, ill-defined, and underaddressed modifiable risk factor remains a challenge. In this review, we emphasize that the tendency among health care professionals to amalgam all forms of obesity altogether as a single entity may contribute to such difficulties and discrepancies. Obesity is a heterogeneous condition both in terms of causes and health consequences. Attention should be given to 2 prevalent subgroups of individuals: 1) patients who are overweight or moderately obese with excess visceral adipose tissue; and 2) patients with severe obesity, the latter group having distinct additional health issues related to their large body fat mass. The challenge of tackling high-cardiovascular-risk forms of obesity through a combination of personalized clinical approaches and population-based solutions is compounded by the current obesogenic environment and economy. [ABSTRACT FROM AUTHOR]

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, β-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 3 days after surgery was also recruited. Results Despite significant metabolic improvement, T2D participants failed to fully normalize insulin resistance and β-cell dysfunction 3 and 4 days after SG. Our results demonstrate the superiority of DS over SG in terms of short-term improvement in postprandial glucose excursion and β-cell function 3 days 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. [ABSTRACT FROM AUTHOR]

Summary Indirect evidence from human studies suggests that brown adipose tissue (BAT) thermogenesis is fueled predominantly by fatty acids hydrolyzed from intracellular triglycerides (TGs). However, no direct experimental evidence to support this assumption currently exists in humans. The aim of this study was to determine the role of intracellular TG in BAT thermogenesis, in cold-exposed men. Using positron emission tomography with 11 C-acetate and 18 F-fluorodeoxyglucose, we showed that oral nicotinic acid (NiAc) administration, an inhibitor of intracellular TG lipolysis, suppressed the cold-induced increase in BAT oxidative metabolism and glucose uptake, despite no difference in BAT blood flow. There was a commensurate increase in shivering intensity and shift toward a greater reliance on glycolytic muscle fibers without modifying total heat production. Together, these findings show that intracellular TG lipolysis is critical for BAT thermogenesis and provides experimental evidence for a reciprocal role of BAT thermogenesis and shivering in cold-induced thermogenesis in humans. [ABSTRACT FROM AUTHOR]

The demonstration of the presence of metabolically active brown adipose tissue (BAT) in adult humans using positron emission tomography (PET) over the past decade has lead to the rapid development of our knowledge regarding the role of BAT in energy metabolism in animal models and in humans. Although animal models continue to provide highly valuable information regarding the mechanisms regulating BAT development, mass and metabolic functions, these studies led to many assumptions that have been at best only partially verified in humans so far. Combined to some limitations of the current investigation approaches used in humans, this has lead to speculation on the potential role of BAT dysfunction in the development of cardiometabolic disorders and on the potential of BAT metabolic activation to treat these conditions. Here we propose a critical review of the evidence for the implication of BAT in cardiometabolic health. [ABSTRACT FROM AUTHOR]

Objective Free fatty acids (FFAs) cause insulin resistance and are often elevated in obesity. Chronic ingestion of diets rich in saturated fat induces more insulin resistance than diets rich in unsaturated fat, however, it remains unclear whether different FFAs cause distinct levels of insulin resistance in the short-term, which is relevant to the feeding and fasting cycle. Protein kinase C (PKC)-δ is implicated in hepatic insulin resistance. Therefore, we investigated the effects of short-term elevation of fatty acids with different degrees of unsaturation on hepatic insulin action and liver PKC-δ membrane translocation, a marker of activation. Materials/Methods Triglyceride emulsions of Soybean Oil + Heparin (polyunsaturated (POLY)), Olive Oil + Heparin (monounsaturated (MONO)), Lard Oil + Heparin (saturated (SATU)), or saline (SAL) were infused intravenously for 7 h to elevate plasma FFA concentrations ~ 3–4 fold in rats. During the last 2 h of infusion, a hyperinsulinemic–euglycemic clamp with tritiated glucose methodology was performed to examine hepatic and peripheral insulin sensitivity. Results Surprisingly, SATU, MONO, and POLY impaired peripheral insulin sensitivity (glucose utilization divided by insulin) to a similar extent. Furthermore, all lipids induced a similar degree of hepatic insulin resistance compared to SAL. Although there were changes in hepatic content of lipid metabolites, there were no significant differences in liver PKC-δ membrane translocation across fat groups. Conclusions In summary, in the short-term, FFAs with different degrees of unsaturation impair peripheral insulin sensitivity and induce hepatic insulin resistance as well as hepatic PKC-δ translocation to the same extent. [ABSTRACT FROM AUTHOR]

Abstract: Reconstruction of main palaeoenvironmental conditions across the Mid-Cenomanian Event (MCE I) in the hemipelagic Tethyan section of Blieux (Southeast France, Vocontian Basin) is proposed. Quantitative analyses of calcareous nannofossil, ammonoid and clay mineral assemblages have been made and compared with respect to sea level changes and the carbon cycle perturbations. The nannofossil primary productivity, as recorded by nannofossil fluxes and relative abundances of meso-eutrophic taxa, is low just below and during the MCE Ia, then slightly increases in the interval including the MCE Ib. The clay assemblages mainly consist of illite/smectite mixed-layers with a smaller proportion of kaolinite. The percentage of kaolinite strongly decreases in the interval including the MCE Ia and slightly increases in the interval including the MCE Ib. The clay assemblages are mainly detrital in origin and reflect environmental changes including differential settling processes, climate, intensity of runoff and detrital sources. The ammonoid assemblages are characterised by a significant change during the MCE I: planispirals (mainly Schloenbachia) are dominant until the MCE Ia, whereas heteromorphs (mainly Sciponoceras) become dominant from the MCE Ib onwards. Strongly oligotrophic levels in sea surfaces are recorded during the MCE Ia and are related both to arid climatic conditions and major sea level fall (both 3rd order and medium scale lowstand deposits). A decrease in bathymetry could partly explain the decrease in the relative abundance of Schloenbachia. The first occurrence of Sciponoceras took place during the MCE Ib; this second positive increase in δ13C is not associated with enhanced nannofossil primary productivity. No clear relations can be established between the occurrence of Sciponoceras and trophic resources. [Copyright &y& Elsevier]

Abstract: A detailed stratigraphic analysis was carried out on the Lower–Middle Cenomanian hemipelagic deposits of the Blieux section (Alpes-de-Haute-Provence; southeast France) in order to identify the Middle Cenomanian event I (MCE I) in the Vocontian Basin. These deposits are represented by five bundles composed of limestone–marl alternations that are separated by thick marly intervals. The Blieux section, which is well exposed, very thick, continuous and relatively rich in macrofauna, provides an ideal succession for an integrated approach. Biostratigraphy by ammonoids and sequence stratigraphy have been established for the whole succession whereas calcareous nannofossil and geochemical analyses have been carried out on a restricted interval across the Lower/Middle Cenomanian boundary. The uppermost part of the Mantelliceras mantelli Zone, the Mantelliceras dixoni Zone and the lower part of the Acanthoceras rhotomagense Zone have been recognized. The appearance of the genus Cunningtoniceras (C. inerme or C. cunningtoni) is used to place the base of the A. rhotomagense Zone and the Lower/Middle Cenomanian boundary. This boundary is also well characterized by the presence of nannofossil Subzone UC2C. Two orders of hierarchically stacked depositional sequences have been identified. Medium- and large-scale sequences correspond to 400 ky eccentricity cycles and to third-order cycles, respectively. The duration of the interval studied (from the uppermost part of the M. mantelli to the lower part of the A. rhotomagense zones) is estimated to be 2.8 my. Carbon-isotope values determined from bulk carbonate sediments show a first positive excursion (+0.6‰) corresponding to the MCE Ia, in the lower part of the A. rhotomagense Zone. A subsequent increase (+1.1‰) is recorded and could correspond to MCE Ib, but a sharp return to baseline values as expected in an excursion is not observed. The duration of the MCE I is estimated to be less than 400 ky. The Blieux section is correlated with some classical sections of the Anglo-Paris (Southerham, Folkestone, Cap Blanc-Nez) and Lower Saxony (Baddeckenstedt and Wunstorf) basins using ammonoid biostratigraphy, sequence stratigraphy, and chemostratigraphy. It is proposed as a candidate for the Middle Cenomanian GSSP (Global Boundary Stratotype Section and Point). [Copyright &y& Elsevier]

Abstract: The objective of the study was to examine if decreases in resting metabolic rate (RMR) take place early in the weight loss process and if they remain throughout the duration of the weight loss intervention. Twenty obese postmenopausal women (61.8 ± 5.9 years) participated in a 15-week weight loss program. After the fifth week, subjects were characterized as having an increased (>5%) or a decreased (<5%) RMR based on baseline values. Afterward, they were followed for an additional 10 weeks. Outcome measures were as follows: fat mass ([FM] total, trunk), lean body mass (total, trunk), RMR, resting heart rate (RHR), and physical activity level. After 5 weeks, significant decreases were observed for lean body mass, FM, and RHR (P < .05), whereas no overall changes in physical activity level and RMR were observed. However, on an individual basis, large variations in RMR were observed (ranging from −320 to +330 kcal/d). Analyses showed that subjects characterized as either having an increased or a decreased RMR after the fifth week maintained these adaptations at the end of intervention. Finally, subjects displaying a decreased RMR during weight loss had a significantly higher RMR and lower FM accumulations at baseline (total and trunk) compared with those with an increased RMR. Interindividual variations in RMR took place early in the weight loss process and were maintained over the duration of the weight loss program in our cohort of obese postmenopausal women. Baseline RMR, changes in RHR, and FM accumulations (total and trunk) seem to be important factors to consider when studying the effects of weight loss on RMR. [Copyright &y& Elsevier]

Abstract: Polyunsaturated fatty acids (PUFAs) have been shown to be immunosuppressive. In particular, they can decrease important T-cell functions that may have a profound impact on the acquired immune response. Several mechanisms may explain the immunosuppressive properties of PUFAs. Here we review the mechanisms by which they interfere with T-cell activation. PUFAs affect lipid rafts composition and function that play an essential role in T-cell signalling. The possible physiological and pathological significances of this immunomodulation by PUFAs are discussed. Further mechanistic studies and randomized controlled clinical trials are needed to assess more accurately their effects in healthy and pathological states. [Copyright &y& Elsevier]

Objective: To determine the effect of reducing insulin secretion on hyperandrogenemia in lean normoinsulinemic women with polycystic ovary syndrome (PCOS) and normal metabolic insulin sensitivity.Design: Transversal assessment at baseline and prospective follow-up of lean PCOS group after 8 days of diazoxide, which reduces insulin secretion, and 1 month of leuprolide, which suppresses LH.Setting: Clinical research center of an academic hospital.Patient(s): Nine lean women (body mass index Intervention(s): Lean PCOS women were reassessed after 8 days of diazoxide and after 1 month of leuprolide, which suppresses LH.Main Outcome Measure(s): Androgen levels and insulin-stimulated glucose disposal (metabolic insulin sensitivity), determined by euglycemic-hyperinsulinemic clamp (M-value).Result(s): Mean M-value of lean PCOS women (48.5 micromol/kg.min) was similar to lean control subjects (52.9 micromol/kg.min). They also had comparable anthropometric measures, lipids, fibrinogen, and plasminogen activator inhibitor 1. The LH did not change significantly after diazoxide, but was almost suppressed after leuprolide in the PCOS group. Androstenedione decreased significantly after diazoxide and even more after leuprolide. However, free T significantly decreased only after diazoxide in lean PCOS women. Diazoxide also increased SHBG significantly in this group.Conclusion(s): In women with typical PCOS and normal insulin levels and metabolic insulin sensitivity, reducing insulin secretion significantly decreased androgen and increased SHBG levels. These results suggest that insulin contributes to hyperandrogenemia even in PCOS women with normal metabolic insulin sensitivity, which might be due to increased sensitivity of their androgenic insulin pathway. [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown suppressive effects of polyunsaturated fatty acids (PUFAs) on T cell proliferation, but the precise mechanism for this effect has not been fully investigated in vivo in humans. Objective: The objective was to determine whether this effect is the result of altered T cell membrane properties and impaired CD3- and CD28-mediated signaling in vivo in humans. Design: Peripheral T cells were isolated from healthy subjects before and 2 h after an intravenous infusion of heparin plus a PUFArich lipid emulsion during a euglycemic hyperinsulinemic clamp to induce a 2.5-fold elevation in plasma linoleic acid concentration without significant change in plasma total free fatty acid concentrations. Results: Intravenous infusion of heparin plus the lipid emulsion reduced peripheral T cell membrane fluidity and altered lipid raft organization, both of which were associated with reduced T cell proliferation after stimulation with CD3 plus CD28. Tyrosine phosphorylation of linker of activated T cells and activation of protein kinase B in T cells were also impaired without a reduction in T cell receptor expression. In addition, acute PUFA elevation was associated with a reduction in T cell membrane cholesterol exchange with the cellular milieu ex vivo. Conclusions: A selective increase in plasma linoleic acid concentration and in intravascular lipolysis has a suppressive effect on peripheral T cell CD28-dependent activation, and this effect is associated with changes in plasma membrane properties. Our results have important implications for nutritional therapy in patients at high risk of septic complications and may also be of relevance to postprandial lipid metabolism disorders such as insulin resistance and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: The use of highly active anti-retroviral therapy (HAART) is associated with long-term adverse metabolic events including lipodystrophy, dyslipidemia, and insulin resistance. The purpose of the present study was to prospectively examine the mechanism of HAART-induced hyperlipidemia in HIV-seropositive, HAART-naïve men prior to the development of frank lipodystrophy. Patient''s (n = 13) weight, BMI, lean mass, and percent fat mass, waist circumference did not change after 8 weeks of treatment with HAART. Plasma FFA concentration was already elevated in HAART-naïve patients compared to healthy, untreated, HIV negative control individuals and was further increased after 8 weeks of HAART in the former. Insulin-mediated suppression of plasma FFA concentrations was impaired both prior to and following introduction of HAART, compared to healthy, matched controls. VLDL-apoB and VLDL-TG concentrations rose significantly from normal levels after HAART. Compared to healthy control subjects, VLDL fractional catabolic rate and clearance in HIV-seropositive individuals was reduced by approximately 40%, a defect that was not corrected after HAART. The increase in VLDL after HAART was explained by an increase of VLDL-apoB and VLDL-TG secretion towards normal while the impaired VLDL clearance remained unchanged. We conclude that elevation of circulating VLDL early in the course of HAART is caused by the combination of impaired VLDL clearance already present in HAART-naïve HIV-seropositive patients and HAART-mediated increase in VLDL secretion. These changes occur concomitantly with an elevation of plasma free fatty acids but before significant change in body composition. [Copyright &y& Elsevier]

Adaptive thermogenesis, which is partly mediated by sympathetic input on brown adipose tissue (BAT), is a mechanism of heat production that confers protection against prolonged cold exposure. Various endogenous stimuli, for example, norepinephrine and FGF-21, can also promote the conversion of inguinal white adipocytes to beige adipocytes, which may represent a secondary cell type that contributes to adaptive thermogenesis. We previously identified an essential role of the molecular scaffold 14-3-3ζ in adipogenesis, but one of the earliest, identified functions of 14-3-3ζ is its regulatory effects on the activity of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of norepinephrine. Herein, we examined whether 14-3-3ζ could influence adaptive thermogenesis via actions on BAT activation or the beiging of white adipocytes. Transgenic mice over-expressing a TAP-tagged human 14-3-3ζ molecule or heterozygous mice without one allele of Ywhaz , the gene encoding 14-3-3ζ, were used to explore the contribution of 14-3-3ζ to acute (3 h) and prolonged (3 days) cold (4 °C) exposure. Metabolic caging experiments, PET-CT imaging, and laser Doppler imaging were used to determine the effect of 14-3-3ζ over-expression on thermogenic and vasoconstrictive mechanisms in response to cold. Transgenic over-expression of 14-3-3ζ (TAP) in male mice significantly improved tolerance to acute and prolonged cold. In response to cold, body temperatures in TAP mice did not decrease to the same extent when compared to wildtype (WT) mice, and this was associated with increased UCP1 expression in beige inguinal white tissue (iWAT) and BAT. Of note was the paradoxical finding that cold-induced changes in body temperatures of TAP mice were associated with significantly decreased energy expenditure. The marked improvements in tolerance to prolonged cold were not due to changes in sensitivity to β-adrenergic stimulation or BAT or iWAT oxidative metabolism; instead, over-expression of 14-3-3ζ significantly decreased thermal conductance and heat loss in mice via increased peripheral vasoconstriction. Despite being associated with elevations in cold-induced UCP1 expression in brown or beige adipocytes, these findings suggest that 14-3-3ζ regulates an alternative, non-thermogenic mechanism via vasoconstriction to minimize heat loss during cold exposure. Image 1 • 14-3-3ζ over-expression in male mice improves tolerance to acute and prolonged cold. • Increasing 14-3-3ζ expression promotes beiging of inguinal white adipose tissue. • Cold-induced changes in body temperature can be dissociated from energy expenditure. • 14-3-3ζ-dependent decreases in heat loss are associated with vasoconstriction. [ABSTRACT FROM AUTHOR]

Abstract: Weight gain and appetite regulation are complex interplays between internal and external cues. Our aim was to investigate the association of eating behaviors with ghrelin taking into account lifestyle. We conducted a cross-sectional analysis in a sample of first-year university students at the Université de Sherbrooke. We collected medical history, anthropometric measurements, vital signs, fitness index, and fasting blood samples. Questionnaires included a lifestyle questionnaire and the Three-Factor Eating Questionnaire (TFEQ) estimating dietary restraint, disinhibition and hunger. We recruited 308 participants aged 20.7±3.2years and a mean BMI of 23.3±3.4kg/m2. Hunger score was significantly associated with ghrelin levels (r=0.11, P <0.05). In women, this association was independent of age, BMI, dietary and lifestyle factors (P =0.02). The association between ghrelin level and hunger score was observable in leaner individuals (r=0.28, p<0.0001) but not in heavier individuals (r=−0.08, p=0.34; stratified by BMI < vs > 22.6kg/m2). Restraint (R) and disinhibition (D) were not associated with ghrelin levels. The three eating behaviors demonstrated expected correlations with lifestyle supporting the validity of the TFEQ in this cohort. In conclusion, we demonstrated that ghrelin, a biological marker, is associated with self-reported perception of hunger, independently of anthropometric measures and lifestyle. [Copyright &y& Elsevier]

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 (β −) emitting radiotracer, was used to characterize the arterial blood input function and myocardial mitochondrial uptake. Afterward, [ 11 C]-acetoacetate (β +) 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 ( K 1 ) and myocardial clearance rate ( k 2 or k mono ) 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 K 1 , k 2 and k mono 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. [ABSTRACT FROM AUTHOR]

Abstract: In 2010, the American Heart Association established the concept of ideal cardiovascular health. Nationally representative data estimated that <1% of Americans meet the seven health metrics required for achieving ideal cardiovascular health, with the main challenge residing in meeting the criteria for an ideal Healthy Diet Score. In a cohort of young adults (N=196), we aimed to investigate the prevalence of ideal cardiovascular health and ideal Healthy Diet Score and its association to weight gain over a 4-year follow-up period. Anthropometric measures, blood pressure, and blood samples were taken according to standardized procedures. Dietary intake was measured by a 3-day food diary and verified by a registered dietitian. We observed that only 0.5% of our sample met the criteria for ideal cardiovascular health and only 4.1% met the criteria for an ideal Healthy Diet Score. The components of the Healthy Diet Score with the lowest observance were consumption of fruits and vegetables (9.7%) and whole grains (14.8%). Meeting zero or one out of five of the Healthy Diet Score components was associated with increased risk of weight gain over 4 years compared with meeting at least two components (P=0.03). With the exception of dietary criteria, prevalence was high for achieving ideal levels of the remaining six cardiovascular health metrics. In conclusion, in this sample of young adults, a very low prevalence of ideal overall cardiovascular health was observed, mainly driven by poor dietary habits, and a poor Healthy Diet Score was associated with increased weight gain. [Copyright &y& Elsevier]

Objective: To assess metabolic and endocrine defects in girls genetically predisposed to polycystic ovary syndrome (PCOS). Design: Controlled cross-sectional study. Setting: University hospital. Patient(s): Nine girls, aged 8–14 years, having a first-degree relative diagnosed with PCOS (PCOSr) and 10 age-matched girls without a family history of PCOS. Intervention(s): None. Main Outcome Measure(s): Insulin sensitivity (ISFSIVGTT) determined by frequently sampled IV glucose tolerance testing (GTT) and insulin-induced nonesterified fatty acid (NEFA) suppression, estimated by the log-linear slope of NEFA levels during the first 20 minutes of GTT. Result(s): In comparison to controls, PCOSr had higher body mass index (BMI) Z-score, waist circumference, and waist-to-height ratio. Levels of the androgen 17α-hydroxyprogesterone (17-OHP) were significantly increased in PCOSr, independent of adiposity, and inversely correlated with ISFSIVGTT. The ISFSIVGTT was decreased and the NEFA suppression was less steep in PCOSr compared with controls, independent of BMI and 17-OHP. The NEFA suppression was more pronounced with increasing ISFSIVGTT, independent of adiposity. Conclusion(s): Girls at high risk of developing PCOS display increased adiposity and 17-OHP levels, but are mainly characterized by global insulin resistance and resistance to insulin-induced suppression of lipolysis that were independent of adiposity and 17-OHP levels. Therefore, genetic predisposition to PCOS may be related to early insulin resistance and adipocyte dysfunction. [ABSTRACT FROM AUTHOR]