Background and objectives: A plant-based diet is an effective strategy in the treatment of obesity. In this 16-week randomized clinical trial, we tested the effect of a plant-based diet on body composition and insulin resistance. As a part of this trial, we investigated the role of plant protein on these outcomes. Subjects and methods: Overweight participants (n = 75) were randomized to follow a plant-based (n = 38) or a control diet (n = 37). Dual X-ray Absorptiometry assessed body composition, Homeostasis Model Assessment (HOMA-IR) assessed insulin resistance, and a linear regression model was used to test the relationship between protein intake, body composition, and insulin resistance. Results: The plant-based vegan diet proved to be superior to the control diet in improving body weight, fat mass, and insulin resistance markers. Only the vegan group showed significant reductions in body weight (treatment effect −6.5 [95% CI −8.9 to −4.1] kg; Gxt, p < 0.001), fat mass (treatment effect −4.3 [95% CI −5.4 to −3.2] kg; Gxt, p < 0.001), and HOMA-IR (treatment effect −1.0 [95% CI −1.2 to −0.8]; Gxt, p = 0.004). The decrease in fat mass was associated with an increased intake of plant protein and decreased intake of animal protein (r = -0.30, p = 0.011; and r = +0.39, p = 0.001, respectively). In particular, decreased % leucine intake was associated with a decrease in fat mass (r = +0.40; p < 0.001), in both unadjusted and adjusted models for changes in BMI and energy intake. In addition, decreased % histidine intake was associated with a decrease in insulin resistance (r = +0.38; p = 0.003), also independent of changes in BMI and energy intake. Conclusions: These findings provide evidence that plant protein, as a part of a plant-based diet, and the resulting limitation of leucine and histidine intake are associated with improvements in body composition and reductions in both body weight and insulin resistance.

Obesity is a global epidemic that greatly increases risk for developing cardiovascular disease and type II diabetes. Sex differences in the obese phenotype are well established in experimental animal models and clinical populations. While having higher adiposity and obesity prevalence, females are generally protected from obesity-related metabolic and cardiovascular complications. This protection is, at least in part, attributed to sex differences in metabolic effects of hormonal mediators such as the renin-angiotensin system (RAS). Previous literature has predominantly focused on the vasoconstrictor arm of the RAS and shown that, in contrast to male rodent models of obesity and diabetes, females are protected from metabolic and cardiovascular derangements produced by angiotensinogen, renin, and angiotensin II. A vasodilator arm of the RAS has more recently emerged which includes angiotensin-(1-7), angiotensin-converting enzyme 2 (ACE2), mas receptors, and alamandine. While accumulating evidence suggests that activation of components of this counter-regulatory axis produces positive effects on glucose homeostasis, lipid metabolism, and energy balance in male animal models, female comparison studies and clinical data related to metabolic outcomes are lacking. This review will summarize current knowledge of sex differences in metabolic effects of the RAS, focusing on interactions with gonadal hormones and potential clinical implications.

Macronutrient composition of the diet influences the development of obesity and insulin resistance. The aim of this study was to assess the role of dietary fat quantity and fatty acid composition in body composition, insulin resistance, and insulin secretion. An open parallel randomized trial design was used. Overweight participants (n = 75) were randomized to follow a low-fat vegan (n = 38) or control diet (n = 37) for 16 weeks. Dual X-ray absorptiometry was used to measure body composition. Insulin resistance was assessed with the Homeostasis Model Assessment (HOMA-IR) index. Insulin secretion was assessed after stimulation with a liquid breakfast (Boost Plus, Nestle, Vevey, Switzerland). Self-reported 3-day diet records were used to assess dietary intake. A linear regression model was used to test the relationship between fat intake and body composition, insulin resistance, and insulin secretion. Changes in fat intake expressed as percent of total energy consumed correlated positively with changes in fat mass (r = 0.52; p < 0.001; and 0.347; p = 0.006, respectively), even after adjustment for changes in body-mass index (BMI) and energy intake (0.33; p = 0.01). Decreased intakes of C18:0 (r = 0.37, p = 0.004) and CLA-trans-10-cis12 (r = 0.40, p = 0.002), but increased intake of C18:2 (r = −0.40, p = 0.002) and C18:3 (p = −0.36, p = 0.006), were associated with a decrease in HOMA-IR, independent on changes in BMI and energy intake. The main fatty acids associated with changes in fasting insulin secretion were C12:0 (r = −0.31, p = 0.03), and TRANS 16:1 (r = −0.33, p = 0.02), both independent on changes in BMI and energy intake. Our findings demonstrate that, in the context of a low-fat vegan diet, decreased intake of saturated and trans fats and increased relative content of polyunsaturated fatty acids, particularly linoleic and α-linolenic acids, are associated with decreased fat mass and insulin resistance, and enhanced insulin secretion.

Apolipoprotein E (APOE) is a lipid transporter produced predominantly by astrocytes in the brain. The ε4 variant of APOE (APOE4) is the strongest and most common genetic risk factor for Alzheimer's disease (AD). Although the molecular mechanisms of this increased risk are unclear, APOE4 is known to alter immune signaling and lipid and glucose metabolism. Astrocytes provide various forms of support to neurons, including regulating neuronal metabolism and immune responses through cytokine signaling. Changes in astrocyte function because of APOE4 may therefore decrease neuronal support, leaving neurons more vulnerable to stress and disease insults. To determine whether APOE4 alters astrocyte neuronal support functions, we measured glycolytic and oxidative metabolism of neurons treated with conditioned media from APOE4 or APOE3 (the common, risk‐neutral variant) primary astrocyte cultures. We found that APOE4 neurons treated with conditioned media from resting APOE4 astrocytes had similar metabolism to APOE3 neurons treated with media from resting APOE3 astrocytes, but treatment with astrocytic conditioned media from astrocytes challenged with amyloid‐β (Aβ), a key pathological protein in AD, caused APOE4 neurons to increase their basal mitochondrial and glycolytic metabolic rates more than APOE3 neurons. These changes were not because of differences in astrocytic lactate production or glucose utilization, but instead correlated with increased glycolytic ATP production and a lack of cytokine secretion in response to Aβ. Additionally, we identified that astrocytic cytokine signatures could predict basal metabolism of neurons treated with the astrocytic conditioned media. Together, these findings suggest that in the presence of Aβ, APOE4 astrocytes alter immune and metabolic functions that result in a compensatory increase in neuronal metabolic stress. image

Tristetraprolin (TTP), encoded by the Zfp36 gene, is a zinc-finger protein that regulates RNA stability primarily through association with 3′ untranslated regions (3′ UTRs) of target mRNAs. While TTP is expressed abundantly in the intestines, its function in intestinal epithelial cells (IECs) is unknown. Here we used a cre-lox system to remove Zfp36 in the mouse epithelium to uncover a role for TTP in IECs and to identify target genes in these cells. While TTP was largely dispensable for establishment and maintenance of the colonic epithelium, we found an expansion of the proliferative zone and an increase in goblet cell numbers in the colon crypts of Zfp36^ΔIEC mice. Furthermore, through RNA-sequencing of transcripts isolated from the colons of Zfp36^fl/fl and Zfp36^ΔIEC mice, we found that expression of inducible nitric oxide synthase (iNos or Nos2) was elevated in TTP-knockout IECs. We demonstrate that TTP interacts with AU-rich elements in the Nos2 3′ UTR and suppresses Nos2 expression. In comparison to control Zfp36^fl/fl mice, Zfp36^ΔIEC mice were less susceptible to dextran sodium sulfate (DSS)-induced acute colitis. Together, these results demonstrate that TTP in IECs targets Nos2 expression and aggravates acute colitis.