Highlights • This manuscript provides an overview of what is known about the role of the gut microbiota in rodent and human energy homeostasis. • This manuscript reviews the differences between ...humans and rodents that may affect the ability to extrapolate conclusions from one order of mammals to the other. • This manuscript suggests future directions of research into the human microbiota that are informed by rodent studies.
Very low-carbohydrate, high-fat ketogenic diets (KDs) induce a pronounced shift in metabolic fuel utilization that elevates circulating ketone bodies; however, the consequences of these compounds for ...host-microbiome interactions remain unknown. Here, we show that KDs alter the human and mouse gut microbiota in a manner distinct from high-fat diets (HFDs). Metagenomic and metabolomic analyses of stool samples from an 8-week inpatient study revealed marked shifts in gut microbial community structure and function during the KD. Gradient diet experiments in mice confirmed the unique impact of KDs relative to HFDs with a reproducible depletion of bifidobacteria. In vitro and in vivo experiments showed that ketone bodies selectively inhibited bifidobacterial growth. Finally, mono-colonizations and human microbiome transplantations into germ-free mice revealed that the KD-associated gut microbiota reduces the levels of intestinal pro-inflammatory Th17 cells. Together, these results highlight the importance of trans-kingdom chemical dialogs for mediating the host response to dietary interventions.
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•Ketogenic diets (KDs) alter the gut microbiota in a manner distinct from high-fat diets•Gut microbial shifts on KDs are driven in part through host production of ketone bodies•β-hydroxybutyrate selectively inhibits bifidobacterial growth•The KD-associated gut microbiota reduces levels of intestinal Th17 cells
Ketogenic diets differ from high fat diets in that they alter the gut microbiome to affect the level of gut Th17 cells.
Endothelial cell (EC) migration is critical for the repair of monolayer disruption following angioplasties, but migration is inhibited by lipid oxidation products, including lysophosphatidylcholine ...(lysoPC), which open canonical transient receptor potential 6 (TRPC6) channels. TRPC6 activation requires an increase in intracellular Ca
concentration (Ca
), the source of which is unknown. LysoPC can activate phospholipase A2 to release arachidonic acid (ArA). ArA can activate arachidonic acid-regulated calcium (ARC) channels that are formed by stromal interaction molecule 1 (STIM1) and Orai1 and Orai3 proteins. Both lysoPC and ArA can activate p38 mitogen-activated protein kinase (MAPK) that induces the phosphorylation required for STIM1-Orai3 association. This is accompanied by an increase in Ca
and TRPC6 externalization. The effect of lysoPC and ArA is not additive, suggesting activation of the same pathway. The increase in Ca
activates an Src kinase that leads to TRPC6 activation. Downregulation of Orai3 using siRNA blocks the lysoPC- or ArA-induced increase in Ca
and TRPC6 externalization and preserves EC migration. These data show that lysoPC induces activation of p38 MAPK, which leads to STIM1-Orai3 association and increased Ca
. This increase in Ca
activates an Src kinase leading to TRPC6 externalization, which initiates a cascade of events ending in cytoskeletal changes that disrupt EC migration. Blocking this pathway preserves EC migration in the presence of lipid oxidation products.
The major lysophospholipid component in oxidized LDL, lysophosphatidylcholine (lysoPC), can activate p38 MAP kinase, which in turn promotes externalization of Orai3 and STIM1-Orai3 association, suggesting involvement of arachidonic acid-regulated calcium (ARC) channels. The subsequent increase in intracellular calcium activates an Src kinase required for TRPC6 externalization. TRPC6 activation, which has been shown to inhibit endothelial cell migration, is blocked by p38 MAP kinase or Orai3 downregulation, and this partially preserves endothelial migration in lysoPC.
Objectives
The National Institutes of Health, led by the National Heart, Lung, and Blood Institute, organized a working group of experts to discuss the problem of weight regain after weight loss. A ...number of experts in integrative physiology and behavioral psychology were convened with the goal of merging their perspectives regarding the barriers to scientific progress and the development of novel ways to improve long‐term outcomes in obesity therapeutics. The specific objectives of this working group were to: (1) identify the challenges that make maintaining a reduced weight so difficult; (2) review strategies that have been used to improve success in previous studies; and (3) recommend novel solutions that could be examined in future studies of long‐term weight control.
Results
Specific barriers to successful weight loss maintenance include poor adherence to behavioral regimens and physiological adaptations that promote weight regain. A better understanding of how these behavioral and physiological barriers are related, how they vary between individuals, and how they can be overcome will lead to the development of novel strategies with improved outcomes.
Conclusions
Greater collaboration and cross‐talk between physiological and behavioral researchers is needed to advance the science and develop better strategies for weight loss maintenance.
A low-error 16S ribosomal RNA amplicon sequencing method, in combination with whole-genome sequencing of >500 cultured isolates, was used to characterize bacterial strain composition in the fecal ...microbiota of 37 U.S. adults sampled for up to 5 years. Microbiota stability followed a power-law function, which when extrapolated suggests that most strains in an individual are residents for decades. Shared strains were recovered from family members but not from unrelated individuals. Sampling of individuals who consumed a monotonous liquid diet for up to 32 weeks indicated that changes in strain composition were better predicted by changes in weight than by differences in sampling interval. This combination of stability and responsiveness to physiologic change confirms the potential of the gut microbiota as a diagnostic tool and therapeutic target.
People with obesity commonly face a pervasive, resilient form of social stigma. They are often subject to discrimination in the workplace as well as in educational and healthcare settings. Research ...indicates that weight stigma can cause physical and psychological harm, and that affected individuals are less likely to receive adequate care. For these reasons, weight stigma damages health, undermines human and social rights, and is unacceptable in modern societies. To inform healthcare professionals, policymakers, and the public about this issue, a multidisciplinary group of international experts, including representatives of scientific organizations, reviewed available evidence on the causes and harms of weight stigma and, using a modified Delphi process, developed a joint consensus statement with recommendations to eliminate weight bias. Academic institutions, professional organizations, media, public-health authorities, and governments should encourage education about weight stigma to facilitate a new public narrative about obesity, coherent with modern scientific knowledge.
•Oxidized lipids selectively activate the PI3K p85α regulatory subunit isoform.•p85α isoform selectively controls lysoPC-induced PI3K membrane translocation.•p85α-mediated PI3K activation by lysoPC ...induces TRPC6 translocation and activation.•p85α siRNA blocks lysoPC-induced Ca2+ influx via TRPC6 and improves EC migration.•p85α is a novel target to promote EC migration and arterial healing after injury.
Activation of phosphatidylinositol 3-kinase (PI3K) by lipid oxidation products, including lysophosphatidylcholine (lysoPC), increases the externalization of canonical transient receptor potential 6 (TRPC6) channels leading to a subsequent increase in intracellular calcium that contributes to cytoskeletal changes which inhibit endothelial cell (EC) migration in vitro and impair EC healing of arterial injuries in vivo. The PI3K p110α and p110δ catalytic subunit isoforms regulate lysoPC-induced TRPC6 externalization in vitro, but have many other functions. The goal of the current study is to identify the PI3K regulatory subunit isoform involved in TRPC6 externalization to potentially identify a more specific treatment regimen to improve EC migration and arterial healing, while minimizing off-target effects. Decreasing the p85α regulatory subunit isoform protein levels, but not the p85β and p55γ regulatory subunit isoforms, with small interfering RNA inhibits lysoPC-induced translocation of the PI3K catalytic subunit to the plasma membrane, dramatically decreased phosphatidylinositol (3,4,5)-trisphosphate (PIP3) production and TRPC6 externalization, and significantly improves EC migration in the presence of lysoPC. These results identify the important and specific role of p85α in controlling translocation of PI3K from the cytosol to the plasma membrane and PI3K-mediated TRPC externalization by oxidized lipids. Current PI3K inhibitors block the catalytic subunit, but our data suggest that the regulatory subunit is a novel therapeutic target to promote EC migration and healing after arterial injuries that occur with angioplasty.
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Objective After arterial injury, endothelial cell (EC) migration is essential for healing, but lipid oxidation products activate TRPC6 and TRPC5 ion channels, leading to increased intracellular ...calcium and inhibition of EC migration in vitro. The objective of this study was to further evaluate the role of TRPC channels in EC migration in vitro and to validate in vitro findings in an in vivo model. Methods Mouse aortic ECs were cultured, and the effect of lysophosphatidylcholine, the major lysophospholipid in oxidized low-density lipoprotein, on migration was assessed in a razor-scrape assay. EC healing after a carotid injury with electrocautery was evaluated in wild-type (WT), TRPC6 −/− , and TRPC5 −/− mice receiving either a chow or high-cholesterol (HC) diet. Results Lysophosphatidylcholine inhibited EC migration of WT ECs to 22% of baseline and of TRPC5 −/− ECs to 53% of baseline but had minimal effect on TRPC6 −/− EC migration. Hypercholesterolemia severely impaired EC healing in vivo, with 51.4% ± 1.8% and 24.9% ± 2.0% of the injury resurfaced with ECs at 5 days in chow-fed and HC-fed WT mice, respectively ( P < .001). Hypercholesterolemia did not impair healing in TRPC6 −/− mice, with coverage of 48.4% ± 3.4% and 46.8% ± 1.6% in chow-fed and HC-fed TRPC6 −/− mice, respectively. Hypercholesterolemia had a reduced inhibitory effect in TRPC5 −/− mice, with EC coverage of 51.7% ± 3.0% and 37.% ± 1.4% in chow-fed and HC-fed TRPC5 −/− mice, respectively. Conclusions Results suggest that activation of TRPC6 and TRPC5 channels is the key contributor to impaired endothelial healing of arterial injuries in hypercholesterolemic mice.
BACKGROUND: After weight loss, total energy expenditure--in particular, energy expenditure at low levels of physical activity--is lower than predicted by actual changes in body weight and ...composition. An important clinical issue is whether this reduction, which predisposes to weight regain, persists over time. OBJECTIVE: We aimed to determine whether this disproportionate reduction in energy expenditure persists in persons who have maintained a body-weight reduction of greater-than-or-equal10% for >1 y. DESIGN: Seven trios of sex- and weight-matched subjects were studied in an in-patient setting while receiving a weight-maintaining liquid formula diet of identical composition. Each trio consisted of a subject at usual weight (Wtinitial), a subject maintaining a weight reduction of greater-than-or-equal10% after recent (5-8 wk) completion of weight loss (Wtloss₋recent), and a subject who had maintained a documented reduction in body weight of >10% for >1 y (Wtloss₋sustained). Twenty-four-hour total energy expenditure (TEE) was assessed by precise titration of fed calories of a liquid formula diet necessary to maintain body weight. Resting energy expenditure (REE) and the thermic effect of feeding (TEF) were measured by indirect calorimetry. Nonresting energy expenditure (NREE) was calculated as NREE = TEE - (REE +TEF). RESULTS: TEE, NREE, and (to a lesser extent) REE were significantly lower in the Wtloss₋sustained and Wtloss₋recent groups than in the Wtinitial group. Differences from the Wtinitial group in energy expenditure were qualitatively and quantitatively similar after recent and sustained weight loss. CONCLUSION: Declines in energy expenditure favoring the regain of lost weight persist well beyond the period of dynamic weight loss.
The carbohydrate-insulin model of obesity posits that habitual consumption of a high-carbohydrate diet sequesters fat within adipose tissue because of hyperinsulinemia and results in adaptive ...suppression of energy expenditure (EE). Therefore, isocaloric exchange of dietary carbohydrate for fat is predicted to result in increased EE, increased fat oxidation, and loss of body fat. In contrast, a more conventional view that "a calorie is a calorie" predicts that isocaloric variations in dietary carbohydrate and fat will have no physiologically important effects on EE or body fat.
We investigated whether an isocaloric low-carbohydrate ketogenic diet (KD) is associated with changes in EE, respiratory quotient (RQ), and body composition.
Seventeen overweight or obese men were admitted to metabolic wards, where they consumed a high-carbohydrate baseline diet (BD) for 4 wk followed by 4 wk of an isocaloric KD with clamped protein. Subjects spent 2 consecutive days each week residing in metabolic chambers to measure changes in EE (EEchamber), sleeping EE (SEE), and RQ. Body composition changes were measured by dual-energy X-ray absorptiometry. Average EE during the final 2 wk of the BD and KD periods was measured by doubly labeled water (EEDLW).
Subjects lost weight and body fat throughout the study corresponding to an overall negative energy balance of ∼300 kcal/d. Compared with BD, the KD coincided with increased EEchamber (57 ± 13 kcal/d, P = 0.0004) and SEE (89 ± 14 kcal/d, P < 0.0001) and decreased RQ (-0.111 ± 0.003, P < 0.0001). EEDLW increased by 151 ± 63 kcal/d (P = 0.03). Body fat loss slowed during the KD and coincided with increased protein utilization and loss of fat-free mass.
The isocaloric KD was not accompanied by increased body fat loss but was associated with relatively small increases in EE that were near the limits of detection with the use of state-of-the-art technology. This trial was registered at clinicaltrials.gov as NCT01967563.
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