Heterogeneity in the effect of marked weight loss on metabolic function in women with obesity

BACKGROUNDThere is considerable heterogeneity in the effect of weight loss on metabolic function in people with obesity.METHODSWe evaluated muscle and liver insulin sensitivity, body composition, and circulating factors associated with insulin action before and after approximately 20% weight loss in women identified as Responders (n = 11) or Non-responders (n = 11), defined as the top (\u3e75% increase) and bottom (\u3c5% increase) quartiles of the weight loss-induced increase in glucose disposal rate (GDR) during a hyperinsulinemic-euglycemic clamp procedure, among 43 women with obesity (BMI: 44.1 ± 7.9 kg/m2).RESULTSAt baseline, GDR, which provides an index of muscle insulin sensitivity, and the hepatic insulin sensitivity index were more than 50% lower in Responders than Non-responders, but both increased much more after weight loss in Responders than Non-responders, which eliminated the differences between groups. Weight loss also caused greater decreases in intrahepatic triglyceride content and plasma adiponectin and PAI-1 concentrations in Responders than Non-responders and greater insulin-mediated suppression of plasma free fatty acids, branched-chain amino acids, and C3/C5 acylcarnitines in Non-responders than Responders, so that differences between groups at baseline were no longer present after weight loss. The effect of weight loss on total body fat mass, intra-abdominal adipose tissue volume, adipocyte size, and circulating inflammatory markers were not different between groups.CONCLUSIONThe results from our study demonstrate that the heterogeneity in the effects of marked weight loss on muscle and hepatic insulin sensitivity in people with obesity is determined by baseline insulin action, and reaches a ceiling when normal insulin action is achieved.TRIAL REGISTRATIONNCT00981500, NCT01299519, NCT02207777.FUNDINGNIH grants P30 DK056341, P30 DK020579, P30 DK052574, UL1 TR002345, and T32 HL13035, the American Diabetes Association (1-18-ICTS-119), the Longer Life Foundation (2019-011), and the Atkins Philanthropic Trust

Effects of diet versus gastric bypass on metabolic function in diabetes

BackgroundSome studies have suggested that in people with type 2 diabetes, Roux-en-Y gastric bypass has therapeutic effects on metabolic function that are independent of weight loss.MethodsWe evaluated metabolic regulators of glucose homeostasis before and after matched (approximately 18%) weight loss induced by gastric bypass (surgery group) or diet alone (diet group) in 22 patients with obesity and diabetes. The primary outcome was the change in hepatic insulin sensitivity, assessed by infusion of insulin at low rates (stages 1 and 2 of a 3-stage hyperinsulinemic euglycemic pancreatic clamp). Secondary outcomes were changes in muscle insulin sensitivity, beta-cell function, and 24-hour plasma glucose and insulin profiles.ResultsWeight loss was associated with increases in mean suppression of glucose production from baseline, by 7.04 μmol per kilogram of fat-free mass per minute (95% confidence interval [CI], 4.74 to 9.33) in the diet group and by 7.02 μmol per kilogram of fat-free mass per minute (95% CI, 3.21 to 10.84) in the surgery group during clamp stage 1, and by 5.39 (95% CI, 2.44 to 8.34) and 5.37 (95% CI, 2.41 to 8.33) μmol per kilogram of fat-free mass per minute in the two groups, respectively, during clamp stage 2; there were no significant differences between the groups. Weight loss was associated with increased insulin-stimulated glucose disposal, from 30.5±15.9 to 61.6±13.0 μmol per kilogram of fat-free mass per minute in the diet group and from 29.4±12.6 to 54.5±10.4 μmol per kilogram of fat-free mass per minute in the surgery group; there was no significant difference between the groups. Weight loss increased beta-cell function (insulin secretion relative to insulin sensitivity) by 1.83 units (95% CI, 1.22 to 2.44) in the diet group and by 1.11 units (95% CI, 0.08 to 2.15) in the surgery group, with no significant difference between the groups, and it decreased the areas under the curve for 24-hour plasma glucose and insulin levels in both groups, with no significant difference between the groups. No major complications occurred in either group.ConclusionsIn this study involving patients with obesity and type 2 diabetes, the metabolic benefits of gastric bypass surgery and diet were similar and were apparently related to weight loss itself, with no evident clinically important effects independent of weight loss. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT02207777.)

Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology

Objective: Individuals with obesity and type 2 diabetes differ from lean and healthy individuals in their abundance of certain gut microbial species and microbial gene richness. Abundance of Akkermansia muciniphila, a mucin-degrading bacterium, has been inversely associated with bodyfat mass and glucose intolerance in mice, but more evidence is needed in humans. The impact of diet and weight loss on this bacterial species is unknown. Our objective was to evaluate the association between fecal A. muciniphila abundance, fecal microbiome gene richness, diet, host characteristics, and their changes after calorie restriction (CR). Design: The intervention consisted of a 6-week CR period followed by a 6-week weight stabilization (WS) diet in overweight and obese adults (N=49, including 41 women). Fecal A. muciniphila abundance, fecal microbial gene richness, diet and bioclinical parameters were measured at baseline and after CR and WS. Results: At baseline A. muciniphila was inversely related to fasting glucose, waist-to-hip ratio, and subcutaneous adipocyte diameter. Subjects with higher gene richness and A. muciniphila abundance exhibited the healthiest metabolic status, particularly in fasting plasma glucose, plasma triglycerides and body fat distribution. Individuals with higher baseline A. muciniphila displayed greater improvement in insulin sensitivity markers and other clinical parameters after CR. A. muciniphila was associated with microbial species known to be related to health. Conclusion: A. muciniphila is associated with a healthier metabolic status and better clinicaloutcomes after CR in overweight/obese adults, however the interaction between gut microbiota ecology and A. muciniphila has to be taken into account

Specific roles of phosphatidylglycerols in hosts and microbes

International audiencePhosphatidylglycerols (PGs) are specific phospholipids bearing negatively charged polar headgroups. Although recognized for long as a major lipid component of membranes in bacteria, it is considered a minor lipid in higher eukaryotes, due to its low abundance in biological fluids or tissues. However, new sensitive lipidomic approaches now provide tools for accurate quantification of PGs in biological samples, and this is likely to uncover new roles for these phospholipids in the near future. This paper reviews our present knowledge in PG function, from studies in microbes and eukaryotic cells, and gathers in one place a diverse range of information spread across many fields. The physical properties of PGs, their biological distribution and molecular functions make them potential actors in host-microbe interaction

Specific roles of phosphatidylglycerols in hosts and microbes

International audiencePhosphatidylglycerols (PGs) are specific phospholipids bearing negatively charged polar headgroups. Although recognized for long as a major lipid component of membranes in bacteria, it is considered a minor lipid in higher eukaryotes, due to its low abundance in biological fluids or tissues. However, new sensitive lipidomic approaches now provide tools for accurate quantification of PGs in biological samples, and this is likely to uncover new roles for these phospholipids in the near future. This paper reviews our present knowledge in PG function, from studies in microbes and eukaryotic cells, and gathers in one place a diverse range of information spread across many fields. The physical properties of PGs, their biological distribution and molecular functions make them potential actors in host-microbe interaction

Perinatal Overnutrition Exacerbates Adipose Tissue Inflammation Caused by High-Fat Feeding in C57BL/6J Mice

<div><p>Obesity causes white adipose tissue (WAT) inflammation and insulin resistance in some, but not all individuals. Here, we used a mouse model of early postnatal overfeeding to determine the role of neonatal nutrition in lifelong WAT inflammation and metabolic dysfunction. C57BL/6J mice were reared in small litters of 3 (SL) or normal litters of 7 pups (NL) and fed either regular chow or a 60% high fat diet (HFD) from 5 to 17 weeks. At weaning, SL mice did not develop WAT inflammation despite increased fat mass, although there was an up-regulation of WAT <i>Arg1</i> and <i>Tlr4</i> expression. On HFD, adult SL mice had greater inguinal fat mass compared to NL mice, however both groups showed similar increases in visceral fat depots and adipocyte hypertrophy. Despite the similar levels of visceral adiposity, SL-HFD mice displayed greater impairments in glucose homeostasis and more pronounced hepatic steatosis compared to NL-HFD mice. In addition, WAT from SL mice fed a HFD displayed greater crown-like structure formation, increased M1 macrophages, and higher cytokine gene expression. Together, these data suggest that early postnatal overnutrition may be a critical determinant of fatty liver and insulin resistance in obese adults by programming the inflammatory capacity of adipose tissue.</p></div

Neonatal overfeeding promotes rapid weight gain and increases adiposity without causing WAT inflammation at weaning.

<p><i>A</i>: Pre-weaning growth curves (body weights) of mice raised in normal litters (NL) or small litters (SL) <b>(</b><i>n</i> = 19–25 per group from ≥ 9 litters). <i>B-C</i>: Mass (<i>B</i>) and mean adipocyte areas (<i>C</i>) of epididymal (eWAT) and subcutaneous (sWAT) adipose tissue of P21 SL and NL mice <b>(</b><i>n</i> = 4–5 per group from ≥ 5 litters). <i>D-E</i>: Representative images showing adipocyte morphology (immunostained for perilipin, <i>green</i> fluorescence) and F4/80-immunoreactive cells (<i>red</i> fluorescence) in eWAT (<i>D</i>) and sWAT (<i>E</i>) of NL and SL mice at P21. <i>F</i>: Quantification of F4/80-immunoreactive cells in eWAT (<i>D</i>) and sWAT (<i>E</i>) of NL and SL mice at P21 <b>(</b><i>n</i> = 4–5 per group from ≥ 4 litters). <i>G-H</i>: Relative gene expression of macrophage markers (<i>G</i>) and cytokines (<i>H</i>) in sWAT at P21. <i>I-K</i>: Plasma levels of TNF-α (<i>I</i>), glucose (<i>J</i>), and insulin (<i>K</i>) in NL and SL mice at P21 <b>(</b><i>n</i> = 4–5 per group from ≥ 4 litters). *<i>P</i><0.05 and **<i>P</i><0.01 versus NL. Scale bar, 100 μm.</p

Neonatal overnutrition exacerbates HFD-induced adipose tissue inflammation.

<p><i>A</i>: Representative images of F4/80 immunoreactivity (<i>red</i> fluorescence) in the epididymal adipose tissue of NL and SL mice fed a chow diet. <i>B</i>: Representative images of F4/80 immunoreactivity (<i>red</i> fluorescence) in the epididymal, retroperitoneal, and inguinal adipose tissue of NL and SL mice fed a high-fat diet (HFD). <i>C</i>: Quantification of crown-like structures (CLS) in the epididymal (eWAT), retroperitoneal (rWAT), and inguinal (iWAT) adipose tissue of adult NL and SL mice fed a HFD (<i>n</i> = 9–13 per group from ≥ 6 litters). <i>D</i>: Representative scatterplots showing CD301 and CD11c heterogeneity in CD45⁺CD64⁺ macrophages from eWAT of adult NL and SL fed a chow or a HFD. <i>E</i>: Histological illustration of antibodies used for flow cytometry. <i>F</i>: Quantification of CD45⁺CD64⁺ total macrophages, CD45⁺CD64⁺CD11c⁺ M1 macrophages and CD45⁺CD64⁺CD301⁺ M2 macrophages in eWAT of SL and NL fed a chow or a HFD (<i>n</i> = 7–8 per group from ≥ 4 litters). *<i>P</i><0.05, **<i>P</i><0.01 and ***<i>P</i><0.001 versus NL matched for diet; Δ <i>P</i><0.05 for diet main-effect. Scale bar, 100 μm.</p

Neonatal overnutrition perturbs glucose homeostasis and causes hepatic steatosis in diet-induced obesity.

<p><i>A-B</i>: Glucose and (<i>A</i>) insulin (<i>B</i>) tolerance tests and incremental area under the curves/inverted incremental area under the curves of adult SL and NL mice fed a chow or a high-fat diet (HFD) (<i>n</i> = 4–10 per group from ≥ 4 litters). <i>C-E</i>: Plasma levels of glucose (<i>C</i>), insulin (<i>D</i>), and hepatic triglyceride content (<i>E</i>) of adult SL and NL mice fed a chow or a HFD (<i>n</i> = 5–11 per group from ≥ 5 litters). <i>F</i>: Representative images showing Oil Red-O stain in the liver of adult SL and NL mice fed a chow or a HFD. *<i>P</i><0.05, **<i>P</i><0.01 and ***<i>P</i><0.001 versus NL matched for diet; ΔΔ <i>P</i><0.01 for diet main-effect. Scale bar, 100 μm.</p

Neonatal overnutrition exacerbates HFD-induced expression of pro-inflammatory genes.

<p><i>A-B</i>: Relative gene expression pro-inflammatory (<i>A</i>) and anti-inflammatory (<i>B</i>) markers in eWAT of NL and SL fed a high-fat diet (HFD) (<i>n</i> = 5–8 per group from 5–8 litters). <i>C</i>: Serum concentrations of adipokines/cytokines (<i>n</i> = 4–8 per group from ≥ 4 litters). *<i>P</i><0.05 and **<i>P</i><0.01 versus NL-HFD; ΔΔ <i>P</i><0.01, ΔΔΔ <i>P</i><0.001 for Diet main-effect.</p