Camu-Camu Reduces Obesity and Improves Diabetic Profiles of Obese and Diabetic Mice: A Dose-Ranging Study.

Overweight, obesity, and their comorbidities are currently considered a major public health concern. Today considerable efforts are still needed to develop efficient strategies able to attenuate the burden of these diseases. Nutritional interventions, some with plant extracts, present promising health benefits. In this study, we evaluated the action of Camu-Camu (Myrciaria dubia), an Amazonian fruit rich in polyphenols and vitamin C, on the prevention of obesity and associated disorders in mice and the abundance of Akkermansia muciniphila in both cecum and feces. Methods: We investigated the dose-response effects of Camu-Camu extract (CCE) in the context of high-fat-diet (HFD)-induced obesity. After 5 weeks of supplementation, we demonstrated that the two doses of CCE differently improved glucose and lipid homeostasis. The lowest CCE dose (62.5 mg/kg) preferentially decreased non-HDL cholesterol and free fatty acids (FFA) and increased the abundance of A. muciniphila without affecting liver metabolism, while only the highest dose of CCE (200 mg/kg) prevented excessive body weight gain, fat mass gain, and hepatic steatosis. Both doses decreased fasting hyperglycemia induced by HFD. In conclusion, the use of plant extracts, and particularly CCE, may represent an additional option in the support of weight management strategies and glucose homeostasis alteration by mechanisms likely independent from the modulation of A. muciniphila abundance.

New targets for NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease worldwide. It is characterised by steatosis, liver inflammation, hepatocellular injury and progressive fibrosis. Several preclinical models (dietary and genetic animal models) of NAFLD have deepened our understanding of its aetiology and pathophysiology. Despite the progress made, there are currently no effective treatments for NAFLD. In this review, we will provide an update on the known molecular pathways involved in the pathophysiology of NAFLD and on ongoing studies of new therapeutic targets.

Gut microbiome, endocrine control of gut barrier function and metabolic diseases.

Overweight and obesity are associated with several cardiometabolic risk factors, including insulin resistance, type 2 diabetes, low-grade inflammation and liver diseases. The gut microbiota is a potential contributing factor regulating energy balance. However, although the scientific community acknowledges that the gut microbiota composition and its activity (e.g. production of metabolites and immune-related compounds) are different between healthy subjects and subjects with overweight/obesity, the causality remains insufficiently demonstrated. The development of low-grade inflammation and related metabolic disorders has been connected with metabolic endotoxaemia and increased gut permeability. However, the mechanisms acting on the regulation of the gut barrier and eventually cardiometabolic disorders are not fully elucidated. In this review, we debate several characteristics of the gut microbiota, gut barrier function and metabolic outcomes. We examine the role of specific dietary compounds or nutrients (e.g. prebiotics, probiotics, polyphenols, sweeteners, and a fructose-rich diet) as well as different metabolites produced by the microbiota in host metabolism, and we discuss how they control several endocrine functions and eventually have either beneficial or deleterious effects on host health.

Intestinal NAPE-PLD contributes to short-term regulation of food intake via gut-to-brain axis.

Our objective was to explore the physiological role of the intestinal endocannabinoids in the regulation of appetite upon short-term exposure to high-fat-diet (HFD) and understand the mechanisms responsible for aberrant gut-brain signaling leading to hyperphagia in mice lacking Napepld in the intestinal epithelial cells (IECs). We generated a murine model harboring an inducible NAPE-PLD deletion in IECs (NapepldΔIEC). After an overnight fast, we exposed wild-type (WT) and NapepldΔIEC mice to different forms of lipid challenge (HFD or gavage), and we compared the modification occurring in the hypothalamus, in the vagus nerve, and at endocrine level 30 and 60 min after the stimulation. NapepldΔIEC mice displayed lower hypothalamic levels of N-oleoylethanolamine (OEA) in response to HFD. Lower mRNA expression of anorexigenic Pomc occurred in the hypothalamus of NapepldΔIEC mice after lipid challenge. This early hypothalamic alteration was not the consequence of impaired vagal signaling in NapepldΔIEC mice. Following lipid administration, WT and NapepldΔIEC mice had similar portal levels of glucagon-like peptide-1 (GLP-1) and similar rates of GLP-1 inactivation. Administration of exendin-4, a full agonist of GLP-1 receptor (GLP-1R), prevented the hyperphagia of NapepldΔIEC mice upon HFD. We conclude that in response to lipid, NapepldΔIEC mice displayed reduced OEA in brain and intestine, suggesting an impairment of the gut-brain axis in this model. We speculated that decreased levels of OEA likely contributes to reduce GLP-1R activation, explaining the observed hyperphagia in this model. Altogether, we elucidated novel physiological mechanisms regarding the gut-brain axis by which intestinal NAPE-PLD regulates appetite rapidly after lipid exposure.

Hepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity.

Peroxisome proliferator activated receptor α (PPARα) acts as a fatty acid sensor to orchestrate the transcription of genes coding for rate-limiting enzymes required for lipid oxidation in hepatocytes. Mice only lacking Pparα in hepatocytes spontaneously develop steatosis without obesity in aging. Steatosis can develop into non alcoholic steatohepatitis (NASH), which may progress to irreversible damage, such as fibrosis and hepatocarcinoma. While NASH appears as a major public health concern worldwide, it remains an unmet medical need. In the current study, we investigated the role of hepatocyte PPARα in a preclinical model of steatosis. For this, we used High Fat Diet (HFD) feeding as a model of obesity in C57BL/6 J male Wild-Type mice (WT), in whole-body Pparα- deficient mice (Pparα-/-) and in mice lacking Pparα only in hepatocytes (Pparαhep-/-). We provide evidence that Pparα deletion in hepatocytes promotes NAFLD and liver inflammation in mice fed a HFD. This enhanced NAFLD susceptibility occurs without development of glucose intolerance. Moreover, our data reveal that non-hepatocytic PPARα activity predominantly contributes to the metabolic response to HFD. Taken together, our data support hepatocyte PPARα as being essential to the prevention of NAFLD and that extra-hepatocyte PPARα activity contributes to whole-body lipid homeostasis.

Sphingolipid metabolism in non-alcoholic fatty liver diseases.

Non-alcoholic fatty liver disease (NAFLD) involves a panel of pathologies starting with hepatic steatosis and continuing to irreversible and serious conditions like steatohepatitis (NASH) and hepatocarcinoma. NAFLD is multifactorial in origin and corresponds to abnormal fat deposition in liver. Even if triglycerides are mostly associated with these pathologies, other lipid moieties seem to be involved in the development and severity of NAFLD. That is the case with sphingolipids and more particularly ceramides. In this review, we explore the relationship between NAFLD and sphingolipid metabolism. After providing an analysis of complex sphingolipid metabolism, we focus on the potential involvement of sphingolipids in the different pathologies associated with NAFLD. An unbalanced ratio between ceramides and terminal metabolic products in the liver and plasma promotes weight gain, inflammation, and insulin resistance. In the etiology of NAFLD, some sphingolipid species such as ceramides may be potential biomarkers for NAFLD. We review the clinical relevance of sphingolipids in liver diseases.

Metabolic Effects of a Chronic Dietary Exposure to a Low-Dose Pesticide Cocktail in Mice: Sexual Dimorphism and Role of the Constitutive Androstane Receptor.

BACKGROUND: Epidemiological evidence suggests a link between pesticide exposure and the development of metabolic diseases. However, most experimental studies have evaluated the metabolic effects of pesticides using individual molecules, often at nonrelevant doses or in combination with other risk factors such as high-fat diets. OBJECTIVES: We aimed to evaluate, in mice, the metabolic consequences of chronic dietary exposure to a pesticide mixture at nontoxic doses, relevant to consumers' risk assessment. METHODS: A mixture of six pesticides commonly used in France, i.e., boscalid, captan, chlorpyrifos, thiofanate, thiacloprid, and ziram, was incorporated in a standard chow at doses exposing mice to the tolerable daily intake (TDI) of each pesticide. Wild-type (WT) and constitutive androstane receptor-deficient (CAR-/-) male and female mice were exposed for 52 wk. We assessed metabolic parameters [body weight (BW), food and water consumption, glucose tolerance, urinary metabolome] throughout the experiment. At the end of the experiment, we evaluated liver metabolism (histology, transcriptomics, metabolomics, lipidomics) and pesticide detoxification using liquid chromatography-mass spectrometry (LC-MS). RESULTS: Compared to those fed control chow, WT male mice fed pesticide chow had greater BW gain and more adiposity. Moreover, these WT males fed pesticide chow exhibited characteristics of hepatic steatosis and glucose intolerance, which were not observed in those fed control chow. WT exposed female mice exhibited fasting hyperglycemia, higher reduced glutathione (GSH):oxidized glutathione (GSSG) liver ratio and perturbations of gut microbiota-related urinary metabolites compared to WT mice fed control chow. When we performed these experiments on CAR-/- mice, pesticide-exposed CAR-/- males did not exhibit BW gain or changes in glucose metabolism compared to the CAR-/- males fed control chow. Moreover, CAR-/- females fed pesticide chow exhibited pesticide toxicity with higher BWs and mortality rate compared to the CAR-/- females fed control chow. CONCLUSIONS: To our knowledge, we are the first to demonstrate a sexually dimorphic obesogenic and diabetogenic effect of chronic dietary exposure to a common mixture of pesticides at TDI levels, and to provide evidence for a partial role for CAR in an in vivo mouse model. This raises questions about the relevance of TDI for individual pesticides when present in a mixture. https://doi.org/10.1289/EHP2877.

Dietary oleic acid regulates hepatic lipogenesis through a liver X receptor-dependent signaling.

Olive oil consumption is beneficial for health as it is associated with a decreased prevalence of cancer and cardiovascular diseases. Oleic acid is, by far, the most abundant component of olive oil. Since it can be made through de novo synthesis in animals, it is not an essential fatty acid. While it has become clear that dietary oleic acid regulates many biological processes, the signaling pathway involved in these regulations remains poorly defined. In this work we tested the impact of an oleic acid-rich diet on hepatic gene expression. We were particularly interested in addressing the contribution of Liver X Receptors (LXR) in the control of genes involved in hepatic lipogenesis, an essential process in whole body energy homeostasis. We used wild-type mice and transgenic mice deficient for both α and ß Liver X Receptor isoforms (LXR-/-) fed a control or an oleate enriched diet. We observed that hepatic-lipid accumulation was enhanced as well as the expression of lipogenic genes in the liver of wild-type mice fed the oleate enriched diet. In contrast, none of these changes occurred in the liver of LXR-/- mice. Strikingly, oleate-rich diet reduced cholesterolemia in wild-type mice and induced signs of liver inflammation and damage in LXR-/- mice but not in wild-type mice. This work suggests that dietary oleic acid reduces cholesterolemia while promoting LXR-dependent hepatic lipogenesis without detrimental effects to the liver.