Phenotypic diversity of human adipose tissue-resident NK cells in obesity

Natural killer (NK) cells have emerged as key mediators of obesity-related adipose tissue inflammation. However, the phenotype of NK cell subsets residing in human adipose tissue are poorly defined, preventing a detailed understanding of their role in metabolic disorders. In this study, we applied multicolor flow cytometry to characterize CD56bright and CD56dim NK cells in blood and adipose tissue depots in individuals with obesity and identified surface proteins enriched on adipose tissue-resident CD56bright NK cells. Particularly, we found that adipose tissue harbored clusters of tissue-resident CD56bright NK cells signatured by the expression of CD26, CCR5 and CD63, possibly reflecting an adaptation to the microenvironment. Together, our findings provide broad insights into the identity of NK cells in blood and adipose tissue in relation to obesity.publishedVersio

Relationship between Ketones, Ghrelin, and, Appetite on Isocaloric Diets with Varying Carbohydrate Quality and Amount: Results from a Randomized Controlled Trial in People with Obesity (CARBFUNC)

Background - Low-carbohydrate high-fat (LCHF) diets may suppress the increase in appetite otherwise seen after diet-induced fat loss. However, studies of diets without severe energy restriction are lacking, and the effects of carbohydrate quality relative to quantity have not been directly compared. Objectives - To evaluated short- (3 mo) and long-term (12 mo) changes in fasting plasma concentrations of total ghrelin, β-hydroxybutyrate (βHB), and subjective feelings of appetite on 3 isocaloric eating patterns within a moderate caloric range (2000–2500 kcal/d) and with varying carbohydrate quality or quantity. Methods - We performed a randomized controlled trial of 193 adults with obesity, comparing eating patterns based on “acellular” carbohydrate sources (e.g., flour-based whole-grain products; comparator arm), “cellular” carbohydrate sources (minimally processed foods with intact cellular structures), or LCHF principles. Outcomes were compared by an intention-to-treat analysis using constrained linear mixed modeling. This trial was registered at clinicaltrials.gov as NCT03401970. Results - Of the 193 adults, 118 (61%) and 57 (30%) completed 3 and 12 mo of follow-up. Throughout the intervention, intakes of protein and energy were similar with all 3 eating patterns, with comparable reductions in body weight (5%−7%) and visceral fat volume (12%−17%) after 12 mo. After 3 mo, ghrelin increased significantly with the acellular (mean: 46 pg/mL; 95% CI: 11, 81) and cellular (mean: 54 pg/mL; 95% CI: 21, 88) diets but not with the LCHF diet (mean: 11 pg/mL; 95% CI: −16, 38). Although βHB increased significantly more with the LCHF diet than with the acellular diet after 3 m (mean: 0.16 mmol/L; 95% CI: 0.09, 0.24), this did not correspond to a significant group difference in ghrelin (unless the 2 high-carbohydrate groups were combined [mean: −39.6 pg/mL; 95% CI: −76, −3.3]). No significant between-group differences were seen in feelings of hunger. Conclusions - Modestly energy-restricted isocaloric diets differing in carbohydrate cellularity and amount showed no significant differences in fasting total ghrelin or subjective hunger feelings. An increase in ketones with the LCHF diet to 0.3–0.4 mmol/L was insufficient to substantially curb increases in fasting ghrelin during fat loss

Diets differing in carbohydrate cellularity and amount similarly reduced visceral fat in people with obesity - a randomized controlled trial (CARBFUNC)

publishedVersio

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

Distinct T cell subsets in adipose tissue are associated with obesity

Adipose tissue inflammation is a driving factor for the development of obesity-associated metabolic disturbances, and a role of adipose tissue T cells in initiating the pro-inflammatory signaling is emerging. However, data on human adipose tissue T cells in obesity are limited, reflected by the lack of phenotypic markers to define tissue-resident T cell subsets. In this study, we performed a deep characterization of T cells in blood and adipose tissue depots using multicolor flow cytometry and RNA sequencing. We identified distinct subsets of T cells associated with obesity expressing the activation markers, CD26 and CCR5, and obesity-specific genes that are potentially engaged in activating pro-inflammatory pathway, including ceramide signaling, autophagy, and IL-6 signaling. These findings increase our knowledge on the heterogeneity of T cells in adipose tissue and on subsets that may play a role in obesity-related pathogenesis.publishedVersio

Diets differing in carbohydrate cellularity and amount similarly reduced visceral fat in people with obesity - a randomized controlled trial (CARBFUNC)

Background & aims Visceral adipose tissue (VAT) volume is associated with common lifestyle diseases. Dietary quality, including food matrix and degree of carbohydrate cellularity, as well as the carbohydrate/fat ratio, may influence VAT volume. We aimed to determine the effects of isocaloric diets differing in either “cellularity”, a novel marker of dietary carbohydrate quality, or carbohydrate amount on visceral fat volume and anthropometric measures in adults with obesity. Methods In a randomized controlled trial of 193 people with obesity/central adiposity, we compared changes in VAT volume after 6 and 12 months, measured by abdominal computed tomography, on three isocaloric eating patterns based on “acellular” carbohydrate sources (e.g., flour-based whole-grain products; comparator arm), “cellular” carbohydrate sources (minimally processed foods with intact cellular structures such as fruits, potatoes/tubers, and rice), or low-carbohydrate high-fat (LCHF) principles. Outcomes were compared by an intention-to-treat (ITT) analysis using constrained linear mixed-effects modelling (cLMM) providing baseline-adjusted change scores and proper missing data handling without imputation. Results 78 and 57 participants completed 6 and 12 months, respectively, with similar intakes of energy (females: 1820−2060 kcal, males: 2480−2550 kcal) and protein (16–17 energy percent, E%) throughout the intervention, and only modest reductions in energy from baseline. Reported dietary intakes were 42–44, 41–42, and 11–15 E% carbohydrate and 36–38, 37–38, and 66–70 E% fat in the acellular, cellular and LCHF groups, respectively. There were no significant between-group differences in VAT volume after 6 months (cellular vs. acellular [95% CI]: −55 cm³ [−545, 436]; LCHF vs. acellular [95% CI]: −225 cm³ [−703, 253]) or after 12 months (cellular vs. acellular [95% CI]: −122 cm³ [−757, 514]; LCHF vs. acellular [95% CI]: −317 cm³ [−943, 309]). VAT volume decreased significantly within all groups by 14–18% and 12–17% after 6 and 12 months, respectively. Waist circumference was reduced to a significantly greater degree in the LCHF vs. acellular group at 6 months (LCHF vs. acellular [95% CI]: −2.78 cm [−5.54, −0.017]). Conclusions Despite modest energy restriction, the three isocaloric eating patterns, differing in carbohydrate cellularity and amount, decreased visceral fat volume significantly and to a similar clinically relevant degree

Relationship between ketones, ghrelin, and, appetite on isocaloric diets with varying carbohydrate quality and amount:results from a randomized controlled trial in people with obesity (CARBFUNC)

Abstract Background: Low-carbohydrate high-fat (LCHF) diets may suppress the increase in appetite otherwise seen after diet-induced fat loss. However, studies of diets without severe energy restriction are lacking, and the effects of carbohydrate quality relative to quantity have not been directly compared. Objectives: To evaluated short- (3 mo) and long-term (12 mo) changes in fasting plasma concentrations of total ghrelin, β-hydroxybutyrate (βHB), and subjective feelings of appetite on 3 isocaloric eating patterns within a moderate caloric range (2000–2500 kcal/d) and with varying carbohydrate quality or quantity. Methods: We performed a randomized controlled trial of 193 adults with obesity, comparing eating patterns based on “acellular” carbohydrate sources (e.g., flour-based whole-grain products; comparator arm), “cellular” carbohydrate sources (minimally processed foods with intact cellular structures), or LCHF principles. Outcomes were compared by an intention-to-treat analysis using constrained linear mixed modeling. This trial was registered at clinicaltrials.gov as NCT03401970. Results: Of the 193 adults, 118 (61%) and 57 (30%) completed 3 and 12 mo of follow-up. Throughout the intervention, intakes of protein and energy were similar with all 3 eating patterns, with comparable reductions in body weight (5%−7%) and visceral fat volume (12%−17%) after 12 mo. After 3 mo, ghrelin increased significantly with the acellular (mean: 46 pg/mL; 95% CI: 11, 81) and cellular (mean: 54 pg/mL; 95% CI: 21, 88) diets but not with the LCHF diet (mean: 11 pg/mL; 95% CI: −16, 38). Although βHB increased significantly more with the LCHF diet than with the acellular diet after 3 m (mean: 0.16 mmol/L; 95% CI: 0.09, 0.24), this did not correspond to a significant group difference in ghrelin (unless the 2 high-carbohydrate groups were combined [mean: −39.6 pg/mL; 95% CI: −76, −3.3]). No significant between-group differences were seen in feelings of hunger. Conclusions: Modestly energy-restricted isocaloric diets differing in carbohydrate cellularity and amount showed no significant differences in fasting total ghrelin or subjective hunger feelings. An increase in ketones with the LCHF diet to 0.3–0.4 mmol/L was insufficient to substantially curb increases in fasting ghrelin during fat loss