Adiposity may confound the association between vitamin D and disease risk - a lifecourse Mendelian randomization study.

Background: Vitamin D supplements are widely prescribed to help reduce disease risk. However, this strategy is based on findings using conventional epidemiological methods which are prone to confounding and reverse causation. Methods: In this short report, we leveraged genetic variants which differentially influence body size during childhood and adulthood within a multivariable Mendelian randomization (MR) framework, allowing us to separate the genetically predicted effects of adiposity at these two timepoints in the lifecourse. Results: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), there was strong evidence that higher childhood body size has a direct effect on lower vitamin D levels in early life (mean age: 9.9 years, range = 8.9-11.5 years) after accounting for the effect of the adult body size genetic score (beta = -0.32, 95% CI = -0.54 to -0.10, p=0.004). Conversely, we found evidence that the effect of childhood body size on vitamin D levels in midlife (mean age: 56.5 years, range = 40-69 years) is putatively mediated along the causal pathway involving adulthood adiposity (beta = -0.17, 95% CI = -0.21 to -0.13, p=4.6 × 10-17). Conclusions: Our findings have important implications in terms of the causal influence of vitamin D deficiency on disease risk. Furthermore, they serve as a compelling proof of concept that the timepoints across the lifecourse at which exposures and outcomes are measured can meaningfully impact overall conclusions drawn by MR studies. Funding: This work was supported by the Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1).

Mutation of spexin2 promotes feeding, somatic growth, adiposity, and insulin resistance in zebrafish.

Spexin2 (spx2) is a newly identified gene in vertebrates, but its biological functions remain unclear. In this study, we cloned the full-length cDNA of spx2 in zebrafish. The 288-bp open reading frame encodes a protein of 95 amino acids that contains a 14 amino acids mature peptide. Spx2 is highly expressed in brain and testis. Its expression was significantly downregulated in the hypothalamus after feeding treatment and 7 days of food deprivation. Using a zebrafish spx2-/- mutant line, we observed a greater amount of food intake and changes in mRNA levels of feeding factors. We found that, SPX2 acts as a satiety factor that inhibits food intake by downregulating the expression of agouti-related neuropeptide (agrp). Moreover, spx2 mutant fish exhibited a larger body size, excessive lipid accumulation, and insulin resistance. Taken together, our results revealed that SPX2 functions as a satiety factor involved in energy metabolic regulation in zebrafish.

Adiposity, diabetes, lifestyle factors and risk of gastroesophageal reflux disease: a Mendelian randomization study.

Adiposity, diabetes, and lifestyle factors are linked to gastroesophageal reflux disease (GERD) in observational studies. We conducted a two-sample Mendelian randomization analysis to determine whether those associations are causal. Independent genetic variants associated with body mass index (BMI), waist circumference (with and without adjustment for BMI), type 2 diabetes, smoking, and alcohol, coffee and caffeine consumption at the genome-wide significance level were selected as instrumental variables. Summary-level data for GERD were available from a genome-wide association meta-analysis of 71,522 GERD cases and 261,079 controls of European descent from the UK Biobank and QSkin Sun and Health studies. The odds ratio (OR) of GERD was 1.49 (95% confidence interval (CI), 1.40-1.60) for one standard deviation (SD) increase in BMI, 1.07 (95% CI, 1.04-1.10) for one-unit increase in log-transformed OR of type 2 diabetes, and 1.41 (95% CI, 1.31-1.52) for one SD increase in prevalence of smoking initiation. There were suggestive associations with GERD for higher genetically predicted waist circumference (OR per one SD increase, 1.14, 95% CI, 1.02-1.26) and caffeine consumption (OR per 80 mg increase, 1.08, 95% CI, 1.02-1.15). Genetically predicted waist circumference adjusted for BMI, alcohol or coffee consumption was not associated GERD. This study suggests causal roles of adiposity, diabetes, and smoking, and a possible role of high caffeine consumption in the development of GERD.

Genetically Predicted Adiposity, Diabetes, and Lifestyle Factors in Relation to Diverticular Disease.

BACKGROUND & AIMS: Adiposity, type 2 diabetes, alcohol and coffee consumption, and smoking have been examined in relation to diverticular disease in observational studies. We conducted a Mendelian randomization study to assess the causality of these associations. METHODS: Independent genetic instruments associated with the studied exposures at genome-wide significance were obtained from published genome-wide association studies. Summary-level data for the exposure-associated single nucleotide polymorphisms with diverticular disease were available in the FinnGen consortium (10,978 cases and 149,001 noncases) and the UK Biobank study (12,662 cases and 348,532 noncases). RESULTS: Higher genetically predicted body mass index and genetic liability to type 2 diabetes and smoking initiation were associated with an increased risk of diverticular disease in meta-analyses of results from the two studies. The combined odds ratio of diverticular disease was 1.23 (95% confidence interval [CI], 1.14-1.33; P < .001) for a 1-standard deviation (~4.8 kg/m2) increase in body mass index, 1.04 (95% CI, 1.01-1.07; P = .007) for a 1-unit increase in log-transformed odds ratio of type 2 diabetes, and 1.21 (95% CI, 1.12-1.30; P < .001) for a 1-standard deviation increase in prevalence of smoking initiation. Coffee consumption was not associated with diverticular disease, whereas the association for alcohol consumption largely differed between the 2 studies. CONCLUSIONS: This study strengthens the causal associations of higher body mass index, type 2 diabetes, and smoking with an increased risk of diverticular disease. Coffee consumption is not associated with diverticular disease. Whether alcohol consumption affects the risk of diverticular disease needs further investigation.

Caloric Restriction and Hypothalamic Leptin Gene Therapy Have Differential Effects on Energy Partitioning in Adult Female Rats.

Dieting is a common but often ineffective long-term strategy for preventing weight gain. Similar to humans, adult rats exhibit progressive weight gain. The adipokine leptin regulates appetite and energy expenditure but hyperleptinemia is associated with leptin resistance. Here, we compared the effects of increasing leptin levels in the hypothalamus using gene therapy with conventional caloric restriction on weight gain, food consumption, serum leptin and adiponectin levels, white adipose tissue, marrow adipose tissue, and bone in nine-month-old female Sprague-Dawley rats. Rats (n = 16) were implanted with a cannula in the 3rd ventricle of the hypothalamus and injected with a recombinant adeno-associated virus, encoding the rat gene for leptin (rAAV-Lep), and maintained on standard rat chow for 18 weeks. A second group (n = 15) was calorically-restricted to match the weight of the rAAV-Lep group. Both approaches prevented weight gain, and no differences in bone were detected. However, calorically-restricted rats consumed 15% less food and had lower brown adipose tissue Ucp-1 mRNA expression than rAAV-Lep rats. Additionally, calorically-restricted rats had higher abdominal white adipose tissue mass, higher serum leptin and adiponectin levels, and higher marrow adiposity. Caloric restriction and hypothalamic leptin gene therapy, while equally effective in preventing weight gain, differ in their effects on energy intake, energy expenditure, adipokine levels, and body composition.

Effect of an aqueous extract of Chrysobalanus icaco on the adiposity of Wistar rats fed a high-fat diet.

INTRODUCTION: Objective: the purpose of this study was to investigate the effects of Chrysobalanus icaco on adiposity and its mechanism of action in the gene and protein expression of acetyl-CoA carboxylase (ACC), a key enzyme in lipogenesis. Method: Wistar rats were divided into a regular or control group (CG) and a high-fat diet (HFD) group. HFD was treated with saline or aqueous extract of Chrysobalanus icaco (AECI) for four weeks. Body weight and food intake were assessed. Subcutaneous, retroperitoneal and periepididymal adipose tissue samples were collected and weighed. Adipocytes from periepididymal tissue were isolated and analyzed. The gene and protein expression of ACC in subcutaneous tissue was determined. Results: AECI showed no effect on intake or body weight. However, the weight of the fat pads and the gene and protein expression of ACC were lower, and glucose tolerance was improved. Conclusion: the aqueous extract of Chrysobalanus icaco proved beneficial for the treatment of obesity, preventing fat storage and improving glycemic homeostasis.

INTRODUCCIÓN: Objetivo: el objetivo de este estudio fue investigar los efectos del extracto acuoso de Chrysobalanus icaco (AECI) en la adiposidad y su mecanismo de acción en la expresión génica y proteica de la acetil-CoA-carboxilasa (ACC), una enzima clave para la lipogénesis. Métodos: se usaron ratones macho Wistar que se asignaron a una dieta estándar de control (CG) o a una rica en grasa (HFD). La HFD se trató con solución salina o con extracto acuoso de Chrysobalanus icaco (AECI) durante cuatro semanas. Se evaluaron el peso corporal y el consumo alimentario. Se aislaron y analizaron muestras de tejido adiposo subcutáneo, retroperitoneal y periepididímico. Se determinó la expresión génica y proteica de ACC en el tejido subcutáneo. Resultados: el AECI no mostró ningún efecto sobre la ingesta de alimento y tampoco sobre el peso corporal. Sin embargo, el tratamiento con AECI redujo el peso de los tejidos adiposos y la expresión génica y proteica de ACC, y mejoró también la tolerancia a la glucosa. Conclusión: Chrysobalanus icaco (AECI) resultó ser beneficioso para el tratamiento de la obesidad, previniendo el almacenamiento de grasa y mejorando la homeostasis glucémica.

Effects of gut microbiota on leptin expression and body weight are lessened by high-fat diet in mice.

Aberration in leptin expression is one of the most frequent features in the onset and progression of obesity, but the underlying mechanisms are still unclear and need to be clarified. This study investigated the effects of the absence of gut microbiota on body weight and the expression and promoter methylation of the leptin. Male C57 BL/6 J germ-free (GF) and conventional (CV) mice (aged 4-5 weeks) were fed either a normal-fat diet (NFD) or a high-fat diet (HFD) for 16 weeks. Six to eight mice from each group, at 15 weeks, were administered exogenous leptin for 7 d. Leptin expression and body weight gain in GF mice were increased by NFD with more CpG sites hypermethylated at the leptin promoter, whereas there was no change with HFD, compared with CV mice. Adipose or hepatic expression of genes associated with fat synthesis (Acc1, Fas and Srebp-1c), hydrolysis and oxidation (Atgl, Cpt1a, Cpt1c, Ppar-α and Pgc-1α) was lower, and hypothalamus expression of Pomc and Socs3 was higher in GF mice than levels in CV mice, particularly with NFD feeding. Exogenous leptin reduced body weight in both types of mice, with a greater effect on CV mice with NFD. Adipose Lep-R expression was up-regulated, and hepatic Fas and hypothalamic Socs3 were down-regulated in both types of mice. Expression of fat hydrolysis and oxidative genes (Atgl, Hsl, Cpt1a, Cpt1c, Ppar-α and Pgc-1α) was up-regulated in CV mice. Therefore, the effects of gut microbiota on the leptin expression and body weight were affected by dietary fat intake.

Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition.

Nutrient excess, a major driver of obesity, diminishes hypothalamic responses to exogenously administered leptin, a critical hormone of energy balance. Here, we aimed to identify a physiological signal that arises from excess caloric intake and negatively controls hypothalamic leptin action. We found that deficiency of the gastric inhibitory polypeptide receptor (Gipr) for the gut-derived incretin hormone GIP protected against diet-induced neural leptin resistance. Furthermore, a centrally administered antibody that neutralizes GIPR had remarkable antiobesity effects in diet-induced obese mice, including reduced body weight and adiposity, and a decreased hypothalamic level of SOCS3, an inhibitor of leptin actions. In contrast, centrally administered GIP diminished hypothalamic sensitivity to leptin and increased hypothalamic levels of Socs3. Finally, we show that GIP increased the active form of the small GTPase Rap1 in the brain and that its activation was required for the central actions of GIP. Altogether, our results identify GIPR/Rap1 signaling in the brain as a molecular pathway linking overnutrition to the control of neural leptin actions.

Gene Expression and Cardiometabolic Phenotypes of Vitamin D-Deficient Overweight and Obese Black Children.

Associations between whole blood transcriptome and clinical phenotypes in vitamin D-deficient overweight and obese children can provide insight into the biological effects of vitamin D and obesity. We determined differentially expressed genes (DEGs) in relation to body mass index (BMI) in vitamin D-deficient black children with a BMI ≥ 85th percentile and ascertained the cardiometabolic phenotypes associated with the DEGs. We examined whole-blood transcriptome gene expression by RNA sequencing and cardiometabolic profiling in 41, 10- to 18-year-old children. We found 296 DEGs in association with BMI after adjusting for age, race, sex, and pubertal status. Cardiometabolic phenotypes associated with the BMI-related DEGs, after adjusting for age, sex, pubertal status, and %total body fat, were (i) flow-mediated dilation (marker of endothelial function), (ii) c-reactive protein (marker of inflammation), and (iii) leptin (adipocytokine). Canonical pathways of relevance for childhood obesity and its phenotypes that were significantly associated with the BMI-related DEGs affected immune cell function/inflammation, vascular health, metabolic function, and cell survival/death; several immune and inflammatory pathways overlapped across the three phenotypes. We have identified transcriptome-based biomarkers associated with BMI in vitamin D-deficient, overweight and obese black children. Modulating effects of vitamin D supplementation on these biomarkers and their related phenotypes need further exploration.

Olanzapine Induced Dysmetabolic Changes Involving Tissue Chromium Mobilization in Female Rats.

Atypical antipsychotics, such as olanzapine, are commonly prescribed to patients with schizophrenic symptoms and other psychiatric disorders. However, weight gain and metabolic disturbance cause adverse effects, impair patient compliance and limit clinical utility. Thus, a better understanding of treatment-acquired adverse effects and identification of targets for therapeutic intervention are believed to offer more clinical benefits for patients with schizophrenia. Beyond its nutritional effects, studies have indicated that supplementation of chromium brings about beneficial outcomes against numerous metabolic disorders. In this study, we investigated whether olanzapine-induced weight gain and metabolic disturbance involved chromium dynamic mobilization in a female Sprague-Dawley rat model, and whether a dietary supplement of chromium improved olanzapine-acquired adverse effects. Olanzapine medicated rats experienced weight gain and adiposity, as well as the development of hyperglycemia, hyperinsulinemia, insulin resistance, hyperlipidemia, and inflammation. The olanzapine-induced metabolic disturbance was accompanied by a decrease in hepatic Akt and AMP-activated Protein Kinase (AMPK) actions, as well as an increase in serum interleukin-6 (IL-6), along with tissue chromium depletion. A daily intake of chromium supplements increased tissue chromium levels and thermogenic uncoupling protein-1 (UCP-1) expression in white adipose tissues, as well as improved both post-olanzapine weight gain and metabolic disturbance. Our findings suggest that olanzapine medicated rats showed a disturbance of tissue chromium homeostasis by inducing tissue depletion and urinary excretion. This loss may be an alternative mechanism responsible for olanzapine-induced weight gain and metabolic disturbance.

Heshouwu (Polygonum multiflorum Thunb.) ethanol extract suppresses pre-adipocytes differentiation in 3T3-L1 cells and adiposity in obese mice.

This study investigated whether Heshouwu (Polygonum multiflorum Thunb.) root ethanol extract (PME) has anti-obesity activity using 3T3-L1 cells and high-fat diet (HFD)-induced obese mice. Treatment with PME (5 and 10 µg/mL) dose-dependently suppressed 3T3-L1 pre-adipocyte differentiation to adipocytes and cellular triglyceride contents. In addition, PME inhibited mRNA and protein expression of adipogenic transcription factors such as CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ), which led to down-regulation of fatty acid synthase gene expression. After feeding mice PME (0.05%) with HFD for 12 weeks, their visceral fat mass, size and body weight were significantly reduced compared with the HFD group. Furthermore, PME supplementation significantly up-regulated the PPARα, CPT1, CPT2, UCP1 and HSL mRNA levels compared with the HFD group, whereas it down-regulated expression of the PPARγ and DGAT2 genes. Finally, HFD increased serum leptin, insulin, glucose and insulin and glucose levels; however, PME reversed these changes. These results demonstrated that PME might relieve obesity that occurs via inhibition of adipogenesis and lipogenesis as well as through lipolysis and fatty acid oxidation in 3T3-L1 cells and HFD-induced obese mice.

SORCS1 and SORCS3 control energy balance and orexigenic peptide production.

SORCS1 and SORCS3 are two related sorting receptors expressed in neurons of the arcuate nucleus of the hypothalamus. Using mouse models with individual or dual receptor deficiencies, we document a previously unknown function of these receptors in central control of metabolism. Specifically, SORCS1 and SORCS3 act as intracellular trafficking receptors for tropomyosin-related kinase B to attenuate signaling by brain-derived neurotrophic factor, a potent regulator of energy homeostasis. Loss of the joint action of SORCS1 and SORCS3 in mutant mice results in excessive production of the orexigenic neuropeptide agouti-related peptide and in a state of chronic energy excess characterized by enhanced food intake, decreased locomotor activity, diminished usage of lipids as metabolic fuel, and increased adiposity, albeit at overall reduced body weight. Our findings highlight a novel concept in regulation of the melanocortin system and the role played by trafficking receptors SORCS1 and SORCS3 in this process.

SGK1/FOXO3 Signaling in Hypothalamic POMC Neurons Mediates Glucocorticoid-Increased Adiposity.

Although the central nervous system has been implicated in glucocorticoid-induced gain of fat mass, the underlying mechanisms are poorly understood. The aim of this study was to investigate the possible involvement of hypothalamic serum- and glucocorticoid-regulated kinase 1 (SGK1) in glucocorticoid-increased adiposity. It is well known that SGK1 expression is induced by acute glucocorticoid treatment, but it is interesting that we found its expression to be decreased in the arcuate nucleus of the hypothalamus, including proopiomelanocortin (POMC) neurons, following chronic dexamethasone (Dex) treatment. To study the role of SGK1 in POMC neurons, we produced mice that developed or experienced adult-onset SGK1 deletion in POMC neurons (PSKO). As observed in Dex-treated mice, PSKO mice exhibited increased adiposity and decreased energy expenditure. Mice overexpressing constitutively active SGK1 in POMC neurons consistently had the opposite phenotype and did not experience Dex-increased adiposity. Finally, Dex decreased hypothalamic α-melanocyte-stimulating hormone (α-MSH) content and its precursor Pomc expression via SGK1/FOXO3 signaling, and intracerebroventricular injection of α-MSH or adenovirus-mediated FOXO3 knockdown in the arcuate nucleus largely reversed the metabolic alterations in PSKO mice. These results demonstrate that POMC SGK1/FOXO3 signaling mediates glucocorticoid-increased adiposity, providing new insights into the mechanistic link between glucocorticoids and fat accumulation and important hints for possible treatment targets for obesity.

Platycodon grandiflorus Root Extract Attenuates Body Fat Mass, Hepatic Steatosis and Insulin Resistance through the Interplay between the Liver and Adipose Tissue.

The Platycodon grandiflorus root, a Korean medicinal food, is well known to have beneficial effects on obesity and diabetes. In this study, we demonstrated the metabolic effects of P. grandiflorus root ethanol extract (PGE), which is rich in platycodins, on diet-induced obesity. C57BL/6J mice (four-week-old males) were fed a normal diet (16.58% of kilocalories from fat), high-fat diet (HFD, 60% of kilocalories from fat), and HFD supplemented with 5% (w/w) PGE. In the HFD-fed mice, PGE markedly suppressed the body weight gain and white fat mass to normal control level, with simultaneous increase in the expression of thermogenic genes (such as SIRT1, PPARα, PGC1α, and UCP1), that accompanied changes in fatty acid oxidation (FAO) and energy expenditure. In addition, PGE improved insulin sensitivity through activation of the PPARγ expression, which upregulates adiponectin while decreasing leptin gene expression in adipocytes. Furthermore, PGE improved hepatic steatosis by suppressing hepatic lipogenesis while increasing expression of FAO-associated genes such as PGC1α. PGE normalized body fat and body weight, which is likely associated with the increased energy expenditure and thermogenic gene expression. PGE can protect from HFD-induced insulin resistance, and hepatic steatosis by controlling lipid and glucose metabolism.

Impaired central leptin signaling and sensitivity in rainbow trout with high muscle adiposity.

The hormone leptin has been identified in all vertebrate classes, but its physiological roles in non-mammalian vertebrates are not well defined. To elucidate leptin regulation in energy homeostasis in a teleost fish species, this study compares hypothalamic and pituitary leptin signaling systems in energetically divergent rainbow trout lines selected for low (lean line, LL) and high (fat line, FL) muscle adiposity under feeding and starvation conditions. In fed fish, hypothalamic gene expression and protein density of the full-functional leptin receptor (LepRL), as well as a leptin binding protein (LepBP) expression, are lower in FL than LL fish. The FL fish have also lower activation of leptin-relevant signaling pathways involving protein kinase B (Akt) and extracellular signal-related kinase. These observations suggests impaired central leptin action in FL fish. During fasting, hypothalamic LepRL and LepBP expression, as well as active Akt levels are downregulated after one week, while pituitary LepRL expression is upregulated, in the LL fish only. After four weeks, hypothalamic LepRL protein levels return to normal levels in both fish lines and Akt is reactivated, although not to the same extent in FL as in LL fish, indicating that FL fish have low leptin sensitivity to nutritional changes. Neuropeptide Y and orexin expression is downregulated to similar levels in both fish lines after one-week fasting. The divergent leptin system profiles between the two fish lines demonstrate that phenotypic selection for high muscle adiposity affects leptin endocrinology, indicating regulatory roles for leptin in rainbow trout energy homeostasis.

Chronic Activation of γ2 AMPK Induces Obesity and Reduces ß Cell Function.

Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease.

Brown Adipose YY1 Deficiency Activates Expression of Secreted Proteins Linked to Energy Expenditure and Prevents Diet-Induced Obesity.

Mitochondrial oxidative and thermogenic functions in brown and beige adipose tissues modulate rates of energy expenditure. It is unclear, however, how beige or white adipose tissue contributes to brown fat thermogenic function or compensates for partial deficiencies in this tissue and protects against obesity. Here, we show that the transcription factor Yin Yang 1 (YY1) in brown adipose tissue activates the canonical thermogenic and uncoupling gene expression program. In contrast, YY1 represses a series of secreted proteins, including fibroblast growth factor 21 (FGF21), bone morphogenetic protein 8b (BMP8b), growth differentiation factor 15 (GDF15), angiopoietin-like 6 (Angptl6), neuromedin B, and nesfatin, linked to energy expenditure. Despite substantial decreases in mitochondrial thermogenic proteins in brown fat, mice lacking YY1 in this tissue are strongly protected against diet-induced obesity and exhibit increased energy expenditure and oxygen consumption in beige and white fat depots. The increased expression of secreted proteins correlates with elevation of energy expenditure and promotion of beige and white fat activation. These results indicate that YY1 in brown adipose tissue controls antagonistic gene expression programs associated with energy balance and maintenance of body weight.

Influence of milk fermented with Lactobacillus rhamnosus NCDC 17 alone and in combination with herbal ingredients on diet induced adiposity and related gene expression in C57BL/6J mice.

Obesity has become a major health problem in developed countries and is rapidly catching up in the developing world due to changes in their life style. Dietary incorporation of functional foods, including probiotic fermented milk and herbal ingredients, is being tried to ameliorate metabolic disorders. In the present study, the effect of dietary supplementation of a probiotic (Lactobacillus rhamnosus NCDC 17) fermented milk alone or either of the herbal preparations (Aloe vera/Gymnema sylvestre powders, 1% w/w) on the progression of obesity has been studied in C57BL/6J mice fed with a high fat diet for 12 weeks. At the end of the experimental period, oral administration of L. rhamnosus and herbs resulted in a significant decrease in the body weight, epididymal fat mass, fasting blood glucose and serum insulin levels. Supplementation of the probiotic L. rhamnosus alone and in combination with herbs showed a significant decrease in the adipocyte cell size and an increase in the number. Finally, obesity related adipokines levels were maintained at normal by the treatment groups. Thus, dietary intervention of milk fermented with probiotic L. rhamnosus alone or in combination with any of the herbal preparations seems to show anti-obesity and anti-inflammatory properties.

Hypothalamic PKA regulates leptin sensitivity and adiposity.

Mice lacking the RIIß regulatory subunit of cyclic AMP-dependent protein kinase A (PKA) display reduced adiposity and resistance to diet-induced obesity. Here we show that RIIß knockout (KO) mice have enhanced sensitivity to leptin's effects on both feeding and energy metabolism. After administration of a low dose of leptin, the duration of hypothalamic JAK/STAT3 signalling is increased, resulting in enhanced POMC mRNA induction. Consistent with the extended JAK/STAT3 activation, we find that the negative feedback regulator of leptin receptor signalling, Socs3, is inhibited in the hypothalamus of RIIß KO mice. During fasting, RIIß-PKA is activated and this correlates with an increase in CREB phosphorylation. The increase in CREB phosphorylation is absent in the fasted RIIß KO hypothalamus. Selective inhibition of PKA activity in AgRP neurons partially recapitulates the leanness and resistance to diet-induced obesity of RIIß KO mice. Our findings suggest that RIIß-PKA modulates the duration of leptin receptor signalling and therefore the magnitude of the catabolic response to leptin.

Efficacy of Berberine in Patients with Non-Alcoholic Fatty Liver Disease.

OBJECTIVES: A randomized, parallel controlled, open-label clinical trial was conducted to evaluate the effect of a botanic compound berberine (BBR) on NAFLD. METHODS: A randomized, parallel controlled, open-label clinical trial was conducted in three medical centers (NIH Registration number: NCT00633282). A total of 184 eligible patients with NAFLD were enrolled and randomly received (i) lifestyle intervention (LSI), (ii) LSI plus pioglitazone (PGZ) 15mg qd, and (iii) LSI plus BBR 0.5g tid, respectively, for 16 weeks. Hepatic fat content (HFC), serum glucose and lipid profiles, liver enzymes and serum and urine BBR concentrations were assessed before and after treatment. We also analyzed hepatic BBR content and expression of genes related to glucose and lipid metabolism in an animal model of NAFLD treated with BBR. RESULTS: As compared with LSI, BBR treatment plus LSI resulted in a significant reduction of HFC (52.7% vs 36.4%, p = 0.008), paralleled with better improvement in body weight, HOMA-IR, and serum lipid profiles (all p<0.05). BBR was more effective than PGZ 15mg qd in reducing body weight and improving lipid profile. BBR-related adverse events were mild and mainly occurred in digestive system. Serum and urine BBR concentrations were 6.99ng/ml and 79.2ng/ml, respectively, in the BBR-treated subjects. Animal experiments showed that BBR located favorably in the liver and altered hepatic metabolism-related gene expression. CONCLUSION: BBR ameliorates NAFLD and related metabolic disorders. The therapeutic effect of BBR on NAFLD may involve a direct regulation of hepatic lipid metabolism. TRIAL REGISTRATION: ClinicalTrials.gov NCT00633282.