The Intestinal Microbiome Predicts Weight Loss on a Calorie-Restricted Diet and Is Associated With Improved Hepatic Steatosis.

The microbiome has been shown in pre-clinical and epidemiological studies to be important in both the development and treatment of obesity and metabolic associated fatty liver disease (MAFLD). However, few studies have examined the role of the microbiome in the clinical response to calorie restriction. To explore this area, we performed a prospective study examining the association of the intestinal microbiome with weight loss and change in hepatic steatosis on a calorie-restricted diet.

Gut microbiome profiles associated with steatosis severity in metabolic associated fatty liver disease.

Aim: The microbiome has been shown to be pivotal in the development of metabolic associated fatty liver disease (MAFLD). Few have examined the relationship of the microbiome specifically with steatosis grade. Therefore, our aim was to characterize the association of the microbiome with MAFLD steatosis severity while adjusting for metabolic comorbidities including diabetes.

Acute Effects of Cinnamon Spice on Post-prandial Glucose and Insulin in Normal Weight and Overweight/Obese Subjects: A Pilot Study.

Clinical studies and meta-analyses have supported the notion that consuming cinnamon spice long term can have beneficial effects in individuals with normal glucose homeostasis and varying degrees of glucose intolerance including type 2 diabetes. The objective of this study was to evaluate the acute effect of cinnamon on the post-prandial responses to a typical American breakfast in normal and overweight/obese participants (ClinicalTrials.gov registration No.

California strawberry consumption increased the abundance of gut microorganisms related to lean body weight, health and longevity in healthy subjects.

It was our hypothesis that foods high in polyphenols and fiber have prebiotic activity. This human intervention study aimed to determine if daily consumption of freeze-dried California strawberry powder (SBP) leads to changes in the intestinal microbiota, fecal cholesterol and bile acid (BA) microbial metabolites. Fifteen healthy adults consumed a beige diet+26 g of SBP for 4 weeks, followed by 2 weeks of beige diet only.

A High Protein Calorie Restriction Diet Alters the Gut Microbiome in Obesity.

Background: High protein calorie restriction diets have shown clinical efficacy for obesity, but the mechanisms are not fully known. The intestinal microbiome is a mediator of obesity and preclinical data support an effect of high protein diet (HPD) on the gut microbiome of obesity, but there are few studies in humans.

Methods: To address this, we conducted a dietary intervention trial of 80 overweight and obese subjects who were randomized to a calorie-restricted high protein diet (HPD) (30% calorie intake) or calorie-restricted normal protein diet (NPD) (15%) for 8 weeks.

Hass Avocado Inclusion in a Weight-Loss Diet Supported Weight Loss and Altered Gut Microbiota: A 12-Week Randomized, Parallel-Controlled Trial.

Background: Avocados contain fiber, lutein, and vitamin E, and they are a rich source of MUFAs. The effect of including an avocado daily as part of a hypocaloric weight-loss diet on weight loss is not known.

Objective: The aim of this study was to determine the effect of daily avocado consumption as part of a hypocaloric diet on weight loss, body composition, satiety, biomarkers of inflammation, and intestinal microbiota composition.

Effects of branched-chain amino acids on glucose metabolism in obese, prediabetic men and women: a randomized, crossover study.

Background: Recent studies have shown that circulating branched-chain amino acids (BCAAs) are elevated in obese, insulin-resistant individuals. However, it is not known if supplementation of additional BCAAs will further impair glucose metabolism.

Objectives: The aim of this pilot study was to determine the effects of BCAA supplementation on glucose metabolism in obese, prediabetic individuals.

Vertical Sleeve Gastrectomy Attenuates the Progression of Non-Alcoholic Steatohepatitis in Mice on a High-Fat High-Cholesterol Diet.

Objective: To determine whether vertical sleeve gastrectomy (VSG) attenuates fibrosis in mice on a high-fat high-cholesterol (HFHC) diet.

Background: Bariatric surgery mitigates non-alcoholic steatohepatitis in 85-90% of obese patients. While animal models demonstrate similar results on a high-fat diet, none have observed the effects of bariatric surgery on a combined HFHC diet.

Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice.

Background & Aims: Transmembrane protein 173 (TMEM173 or STING) signaling by macrophage activates the type I interferon-mediated innate immune response. The innate immune response contributes to hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). We investigated whether STING regulates diet-induced in hepatic steatosis, inflammation, and liver fibrosis in mice.

Cyclic GMP-AMP Ameliorates Diet-induced Metabolic Dysregulation and Regulates Proinflammatory Responses Distinctly from STING Activation.

Endogenous cyclic GMP-AMP (cGAMP) binds and activates STING to induce type I interferons. However, whether cGAMP plays any roles in regulating metabolic homeostasis remains unknown. Here we show that exogenous cGAMP ameliorates obesity-associated metabolic dysregulation and uniquely alters proinflammatory responses.

A role for /iPFK2 in metformin suppression of adipocyte inflammatory responses.

Metformin improves obesity-associated metabolic dysregulation, but has controversial effects on adipose tissue inflammation. The objective of the study is to examine the direct effect of metformin on adipocyte inflammatory responses and elucidate the underlying mechanisms. Adipocytes were differentiated from 3T3-L1 cells and treated with metformin at various doses and for different time periods.

Nutritional approaches for managing obesity-associated metabolic diseases.

Obesity is an ongoing pandemic and serves as a causal factor of a wide spectrum of metabolic diseases including diabetes, fatty liver disease, and cardiovascular disease. Much evidence has demonstrated that nutrient overload/overnutrition initiates or exacerbates inflammatory responses in tissues/organs involved in the regulation of systemic metabolic homeostasis. This obesity-associated inflammation is usually at a low-grade and viewed as metabolic inflammation.

Glucose and Palmitate Differentially Regulate PFKFB3/iPFK2 and Inflammatory Responses in Mouse Intestinal Epithelial Cells.

The gene PFKFB3 encodes for inducible 6-phosphofructo-2-kinase, a glycolysis-regulatory enzyme that protects against diet-induced intestine inflammation. However, it is unclear how nutrient overload regulates PFKFB3 expression and inflammatory responses in intestinal epithelial cells (IECs). In the present study, primary IECs were isolated from small intestine of C57BL/6J mice fed a low-fat diet (LFD) or high-fat diet (HFD) for 12 weeks.

Berberine Ameliorates Hepatic Steatosis and Suppresses Liver and Adipose Tissue Inflammation in Mice with Diet-induced Obesity.

Increasing evidence demonstrates that berberine (BBR) is beneficial for obesity-associated non-alcoholic fatty liver disease (NAFLD). However, it remains to be elucidated how BBR improves aspects of NAFLD. Here we revealed an AMP-activated protein kinase (AMPK)-independent mechanism for BBR to suppress obesity-associated inflammation and improve hepatic steatosis.

Metformin and metabolic diseases: a focus on hepatic aspects.

Metformin has been widely used as a first-line anti-diabetic medicine for the treatment of type 2 diabetes (T2D). As a drug that primarily targets the liver, metformin suppresses hepatic glucose production (HGP), serving as the main mechanism by which metformin improves hyperglycemia of T2D. Biochemically, metformin suppresses gluconeogenesis and stimulates glycolysis.

Aquaporin-11 control of testicular fertility markers in Syrian hamsters.

The present study sought novel changes to the hamster testicular transcriptome during modulation of fertility by well-characterized photoperiodic stimuli. Transition from long days (LD, 14 h light/day) to short days (SD, 10h light/day) triggered testicular regression (61% reduction of testis weight, relative to LD) in SD-sensitive (SD-S) hamsters within 16 weeks. After 22 weeks of SD exposure, a third cohort of hamsters became SD-refractory (SD-R), and exhibited testicular recrudescence (137% testis weight gain, relative to SD-S).

Myeloid cell-specific disruption of Period1 and Period2 exacerbates diet-induced inflammation and insulin resistance.

The circadian clockworks gate macrophage inflammatory responses. Given the association between clock dysregulation and metabolic disorders, we conducted experiments to determine the extent to which over-nutrition modulates macrophage clock function and whether macrophage circadian dysregulation is a key factor linking over-nutrition to macrophage proinflammatory activation, adipose tissue inflammation, and systemic insulin resistance. Our results demonstrate that 1) macrophages from high fat diet-fed mice are marked by dysregulation of the molecular clockworks in conjunction with increased proinflammatory activation, 2) global disruption of the clock genes Period1 (Per1) and Per2 recapitulates this amplified macrophage proinflammatory activation, 3) adoptive transfer of Per1/2-disrupted bone marrow cells into wild-type mice potentiates high fat diet-induced adipose and liver tissue inflammation and systemic insulin resistance, and 4) Per1/2-disrupted macrophages similarly exacerbate inflammatory responses and decrease insulin sensitivity in co-cultured adipocytes in vitro.

Metformin ameliorates hepatic steatosis and inflammation without altering adipose phenotype in diet-induced obesity.

Non-alcoholic fatty liver disease (NAFLD) is closely associated with obesity and insulin resistance. To better understand the pathophysiology of obesity-associated NAFLD, the present study examined the involvement of liver and adipose tissues in metformin actions on reducing hepatic steatosis and inflammation during obesity. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity-associated NAFLD and treated with metformin (150 mg/kg/d) orally for the last four weeks of HFD feeding.

Gly482Ser mutation impairs the effects of peroxisome proliferator-activated receptor γ coactivator-1α on decreasing fat deposition and stimulating phosphoenolpyruvate carboxykinase expression in hepatocytes.

Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a transcriptional coactivator of nuclear receptor peroxisome proliferator-activated receptor γ that critically regulates glucose and fat metabolism. Although clinical evidence suggests that Gly482Ser polymorphism of PGC-1α is associated with an increased incidence of nonalcoholic fatty liver disease, a direct role for Gly482Ser mutation in altering PGC-1α actions on hepatocyte fat deposition remains to be explored. We hypothesized that Gly482Ser mutation impairs the abilities of PGC-1α in ameliorating overnutrition-induced hepatocyte fat deposition and in stimulating hepatocyte expression of cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C; encoded by a key PGC-1α target gene).

A role for inducible 6-phosphofructo-2-kinase in the control of neuronal glycolysis.

Increased glycolysis is the result of the sensing of glucose by hypothalamic neurons. The biochemical mechanisms underlying the control of hypothalamic glycolysis, however, remain to be elucidated. Here we showed that PFKFB3, the gene that encodes for inducible 6-phosphofructo-2-kinase (iPFK2), was expressed at high abundance in both mouse hypothalami and clonal hypothalamic neurons.

Disruption of inducible 6-phosphofructo-2-kinase impairs the suppressive effect of PPARγ activation on diet-induced intestine inflammatory response.

PFKFB3 is a target gene of peroxisome proliferator-activated receptor gamma (PPARγ) and encodes for inducible 6-phosphofructo-2-kinase (iPFK2). As a key regulatory enzyme that stimulates glycolysis, PFKFB3/iPFK2 links adipocyte metabolic and inflammatory responses. Additionally, PFKFB3/iPFK2 is involved in the effect of active PPARγ on suppressing overnutrition-induced adipose tissue inflammatory response, which accounts for the insulin-sensitizing and antidiabetic effects of PPARγ activation.

Palmitoleate induces hepatic steatosis but suppresses liver inflammatory response in mice.

The interaction between fat deposition and inflammation during obesity contributes to the development of non-alcoholic fatty liver disease (NAFLD). The present study examined the effects of palmitoleate, a monounsaturated fatty acid (16:1n7), on liver metabolic and inflammatory responses, and investigated the mechanisms by which palmitoleate increases hepatocyte fatty acid synthase (FAS) expression. Male wild-type C57BL/6J mice were supplemented with palmitoleate and subjected to the assays to analyze hepatic steatosis and liver inflammatory response.

Targeted overexpression of inducible 6-phosphofructo-2-kinase in adipose tissue increases fat deposition but protects against diet-induced insulin resistance and inflammatory responses.

Increasing evidence demonstrates the dissociation of fat deposition, the inflammatory response, and insulin resistance in the development of obesity-related metabolic diseases. As a regulatory enzyme of glycolysis, inducible 6-phosphofructo-2-kinase (iPFK2, encoded by PFKFB3) protects against diet-induced adipose tissue inflammatory response and systemic insulin resistance independently of adiposity. Using aP2-PFKFB3 transgenic (Tg) mice, we explored the ability of targeted adipocyte PFKFB3/iPFK2 overexpression to modulate diet-induced inflammatory responses and insulin resistance arising from fat deposition in both adipose and liver tissues.