Antibiotics administration alleviates the high fat diet-induced obesity through altering the lipid metabolism in young mice

Currently, there is a global trend of rapid increase in obesity, especially among adolescents. The antibiotics cocktails (ABX) therapy is commonly used as an adjunctive treatment for gut microbiota related diseases, including obesity. However, the effects of broad-spectrum antibiotics alone on young obese hosts have rarely been reported. In the present study, the 3-week-old C57BL/6J male mice fed a high-fat diet (HFD) were intragastric administration with ampicillin, vancomycin, metronidazole or neomycin for 30 days. The lipid metabolites in plasma were assessed by biochemical assay kits, and genes related to lipid metabolite in the white adipose were assessed by qPCR. To further analyze the underlying mechanisms, the expression of genes related to lipid metabolism, inflammatory reactions and oxidative stress in the liver were determined by qPCR assay. In addition, the expression of oxidative damage-associated proteins in the liver were detected by western blot. The results showed that oral antibiotics exposure could reduce body weight and fat index in HFD-fed mice, concurrent with the increase of white adipose lipolysis genes and the decrease of hepatic lipogenic genes. Furthermore, antibiotics treatment could clearly reverse the HFD-induced elevation of oxidative damage-related proteins in the liver. Together, these findings will provide valuable clues into the effects of antibiotics on obesity.     

Lutein Prevents High Fat Diet‐Induced Atherosclerosis in ApoE‐Deficient Mice by Inhibiting NADPH Oxidase and Increasing PPAR Expression

Epidemiological and experimental studies provide supportive evidence that lutein, a major carotenoid, may act as a chemopreventive agent against atherosclerosis, although the underlying molecular mechanisms are not well understood. The main aim of this study was to investigate the effects of lutein on the alleviation of atherosclerosis and its molecular mechanisms involved in oxidative stress and lipid metabolism. Male apolipoprotein E knockout mice (n = 55) were fed either a normal chow diet or a high fat diet (HFD) supplemented with or without lutein for 24 weeks. The results showed that a HFD induced atherosclerosis formation, lipid metabolism disorders and oxidative stress, but noticeable improvements were observed in the lutein treated group. Additionally, lutein supplementation reversed the decreased protein expression of aortic heme oxygenase‐1 and increased the mRNA and protein expressions of aortic nicotinamide‐adenine dinucleotide phosphate oxidase stimulated by a HFD. Furthermore, the decreased mRNA and protein expression levels of hepatic peroxisome proliferator‐activated receptor‐α, carnitine palmitoyltransferase 1A, acyl CoA oxidase 1, low density lipoprotein receptors and scavenger receptor class B type I observed in mice with atherosclerosis were markedly enhanced after treatment with lutein. Taken together, these data add new evidence supporting the anti‐atherogenic properties of lutein and describing its mechanisms of action in atherosclerosis prevention, including oxidative stress and lipid metabolism improvements.     

Osteoporosis Due to Hormone Imbalance: An Overview of the Effects of Estrogen Deficiency and Glucocorticoid Overuse on Bone Turnover

Osteoporosis is a serious health issue among aging postmenopausal women. The majority of postmenopausal women with osteoporosis have bone loss related to estrogen deficiency. The rapid bone loss results from an increase in bone turnover with an imbalance between bone resorption and bone formation. Osteoporosis can also result from excessive glucocorticoid usage, which induces bone demineralization with significant changes of spatial heterogeneities of bone at microscale, indicating potential risk of fracture. This review is a summary of current literature about the molecular mechanisms of actions, the risk factors, and treatment of estrogen deficiency related osteoporosis (EDOP) and glucocorticoid induced osteoporosis (GIOP). Estrogen binds with estrogen receptor to promote the expression of osteoprotegerin (OPG), and to suppress the action of nuclear factor-κβ ligand (RANKL), thus inhibiting osteoclast formation and bone resorptive activity. It can also activate Wnt/β-catenin signaling to increase osteogenesis, and upregulate BMP signaling to promote mesenchymal stem cell differentiation from pre-osteoblasts to osteoblasts, rather than adipocytes. The lack of estrogen will alter the expression of estrogen target genes, increasing the secretion of IL-1, IL-6, and tumor necrosis factor (TNF). On the other hand, excessive glucocorticoids interfere the canonical BMP pathway and inhibit Wnt protein production, causing mesenchymal progenitor cells to differentiate toward adipocytes rather than osteoblasts. It can also increase RANKL/OPG ratio to promote bone resorption by enhancing the maturation and activation of osteoclast. Moreover, excess glucocorticoids are associated with osteoblast and osteocyte apoptosis, resulting in declined bone formation. The main focuses of treatment for EDOP and GIOP are somewhat different. Avoiding excessive glucocorticoid use is mandatory in patients with GIOP. In contrast, appropriate estrogen supplement is deemed the primary treatment for females with EDOP of various causes. Other pharmacological treatments include bisphosphonate, teriparatide, and RANKL inhibitors. Nevertheless, more detailed actions of EDOP and GIOP along with the safety and effectiveness of medications for treating osteoporosis warrant further investigation.     

Apolipoprotein CIII Reduction Protects White Adipose Tissues against Obesity-Induced Inflammation and Insulin Resistance in Mice

Apolipoprotein CIII (apoCIII) is proinflammatory and increases in high-fat diet (HFD)-induced obesity and insulin resistance. We have previously shown that reducing apoCIII improves insulin sensitivity in vivo by complex mechanisms involving liver and brown adipose tissue. In this study the focus was on subcutaneous (SAT) and visceral (VAT) white adipose tissue (WAT). Mice were either given HFD for 14 weeks and directly from start also treated with antisense oligonucleotide (ASO) against apoCIII or given HFD for 10 weeks and HFD+ASO for an additional 14 weeks. Both groups had animals treated with inactive (Scr) ASO as controls and in parallel chow-fed mice were injected with saline. Preventing an increase or lowering apoCIII in the HFD-fed mice decreased adipocytes’ size, reduced expression of inflammatory cytokines and increased expression of genes related to thermogenesis and beiging. Isolated adipocytes from both VAT and SAT from the ASO-treated mice had normal insulin-induced inhibition of lipolysis compared to cells from Scr-treated mice. In conclusion, the HFD-induced metabolic derangements in WATs can be prevented and reversed by lowering apoCIII.     

Theophylline-Based KMUP-1 Improves Steatohepatitis via MMP-9/IL-10 and Lipolysis via HSL/p-HSL in Obese Mice

KMUP-1 (7-[2-[4-(2-chlorobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine) has been reported to cause hepatic fat loss. However, the action mechanisms of KMUP-1 in obesity-induced steatohepatitis remains unclear. This study elucidated the steatohepatitis via matrix metallopeptidase 9 (MMP-9) and tumor necrosis factor α (TNFα), and related lipolysis via hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) by KMUP-1. KMUP-1 on steatohepatitis-associated HSL/p-HSL/ATGL/MMP-9/TNFα/interleukin-10 (IL-10) and infiltration of M1/M2 macrophages in obese mice were examined. KMUP-1 was administered by oral gavage from weeks 1–14 in high-fat diet (HFD)-supplemented C57BL/6J male mice (protection group) and from weeks 8–14, for 6 weeks, in HFD-induced obese mice (treatment group). Immunohistochemistry (IHC) and hematoxylin and eosin (H&E) staining of tissues, oil globules number and size, infiltration and switching of M1/M2 macrophages were measured to determine the effects on livers. IL-10 and MMP-9 proteins were explored to determine the effects of KMUP-1 on M1/M2 macrophage polarization in HFD-induced steatohepatitis. Long-term administration of KMUP-1 reversed HFD-fed mice increased in body weight, sGOT/sGPT, triglyceride (TG) and glucose. Additionally, KMUP-1 decreased MMP-9 and reactive oxygen species (ROS), and increased HSL/p-HSL and IL-10 in HFD mice livers. In conclusion, KMUP-1, a phosphodiesterase inhibitor (PDEI), was shown to reduce lipid accumulation in liver tissues, suggesting that it could be able to prevent or treat steatohepatitis induced by HFD.     

Effects of Overexpression of Neurosecretory Protein GL-Precursor Gene on Glucose Homeostasis and Insulin Sensitivity in Mice

A high-fat diet (HFD) quickly induces obesity with insulin resistance and hyperglycemia. We previously reported that a novel hypothalamic small protein, named neurosecretory protein GL (NPGL), stimulates feeding and fat accumulation in mice. However, the effects of NPGL on insulin sensitivity and glucose homeostasis remain unknown. Hence, we subjected NPGL-precursor gene (Npgl)-overexpressing mice to the oral glucose tolerance test (OGTT) and intraperitoneal insulin tolerance test (IPITT) under normal chow (NC) and HFD conditions. Npgl overexpression promoted body mass gain and tended to increase food intake of NC-fed mice, whereas it had little effect on HFD-fed mice. The OGTT showed elevated blood glucose and insulin levels in Npgl-overexpressing NC-fed mice 15 min after glucose administration. Both the OGTT and IPITT demonstrated that Npgl overexpression decreased blood glucose levels in HFD-fed mice 60 min after glucose and insulin treatments. Notably, Npgl overexpression increased adipose tissue masses only in NC-fed mice, and it decreased blood glucose and insulin levels in HFD-fed mice at the experimental end point. It also increased the mRNA expression of galanin, one of the feeding and metabolic regulatory neuropeptides, in the hypothalamus of HFD-fed mice. Therefore, NPGL may alleviate HFD-induced hyperglycemia and insulin resistance in mice.     

Metabolomic Profiles in Adipocytes Differentiated from Adipose-Derived Stem Cells Following Exercise Training or High-Fat Diet

Controlling the differentiation potential of adipose-derived stem cells (ADSCs) is attracting attention as a new strategy for the prevention and treatment of obesity. Here, we aimed to observe the effect of exercise training (TR) and high-fat diet (HFD) on the metabolic profiles of ADSCs-derived adipocytes. The rats were divided into four groups: normal diet (ND)-fed control (ND-SED), ND-fed TR (ND-TR), HFD-fed control (HFD-SED), and HFD-fed TR (HFD-TR). After 9 weeks of intervention, ADSCs of epididymal and inguinal adipose tissues were differentiated into adipocytes. In the metabolome analysis of adipocytes after isoproterenol stimulation, 116 metabolites were detected. The principal component analysis demonstrated that ADSCs-derived adipocytes segregated into four clusters in each fat pad. Amino acid accumulation was greater in epididymal ADSCs-derived adipocytes of ND-TR and HFD-TR, but lower in inguinal ADSCs-derived adipocytes of ND-TR, than in the respective controls. HFD accumulated several metabolites including amino acids in inguinal ADSCs-derived adipocytes and more other metabolites in epididymal ones. Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that TR mainly affected the pathways related to amino acid metabolism, except in inguinal ADSCs-derived adipocytes of HFD-TR rats. These findings provide a new way to understand the mechanisms underlying possible changes in the differentiation of ADSCs due to TR or HFD.     

Gene expression profiling in streptozotocin-induced diabetic rat liver in response to fungal polysaccharide treatment

We established the gene expression profiling in streptozotocin (STZ)-induced diabetic rat liver in response to hypoglycemic fungal polysaccharides (EPS), using oligonucleotide microarray analysis. Differentially regulated genes showing higher fold change than 2 were identified and categorized through hierarchical clustering analysis. Among the 835 genes analyzed, 244 were up-regulated, while 321 were down-regulated after diabetes induction. Interestingly, many gene expressions altered after STZ-treatment mimicked a normal rat liver by EPS therapy. Most of these genes included genes involving cell structure and motility, immunity and defense, lipid, fatty acid and steroid metabolism, protein metabolism and modification, and signal transduction. More importantly, we found a total of 36 genes that showed significant fold changes in their expression that have not previously been examined in the context of diabetes. To validate the microarray results, we further confirmed the gene expression patterns by RT-PCR using four genes of interest (carboxylesterase 2, stearoyl-coenzyme A desaturase 1, insulin-like growth factor 1, and insulin-like growth factor binding protein 2). Taken together, EPS acted as a potent regulator of gene expression for a wide variety of genes in diabetic rat liver.     

Chia Seed Oil Prevents High Fat Diet Induced Hyperlipidemia and Oxidative Stress in Mice

Hyperlipidemia is a common cardiovascular disease. At present, the influence of high fat diet (HFD) on this is being explored. Recently, vegetable oils rich in omega‐3 have been reported that can treat hyperlipidemia caused by HFD. However, the effects of chia seed oil (CSO) on HFD‐induced hyperlipidemia and oxidative stress are poorly studied. Hence, in this study, the effects of CSO on hyperlipidemia and oxidative stress induced by HFD in mice are analyzed by various commercial kits, section staining, and protein expression. The results show that CSO decreases body weight and organ index. Meanwhile, CSO reduces serum lipid levels of total cholesterol, triglyceride, and low‐density lipoprotein cholesterol. It can also elevate superoxide dismutase and glutathione peroxidase activities and reduce malondialdehyde content in serum and liver. The results of histopathological analysis prove that CSO improves hepatic steatosis and reduces lipid deposition. Further, the results of western blot demonstrate that CSO upregulates the expression of peroxisome proliferator‐activated receptor alpha and carnitine palmitoyltransferase 1a in the liver. As a result, CSO may be a potential lipid‐lowering oil to prevent and treat HFD‐induced hyperlipidemia and oxidative stress. Practical Applications CSO, as a byproduct of chia seed processing, is a rich source of α‐linolenic acid. This study investigates the effects of CSO on HFD‐induced hyperlipidemia and oxidative stress in mice. It is concluded that dietary CSO can improve the hyperlipidemia in HFD‐induced mice via analysis of lipid parameters, histopathology study of the liver, and lipid metabolism related genes. In addition, supplementation of CSO also can improve the oxidative stress in mice. Therefore, CSO can be used for the prevention of hyperlipidemia and oxidative stress. This research provides a theoretical basis for the comprehensive development and utilization of functional chia seed oil.     

The Involvement of Long Non-Coding RNAs in Bone

A harmonious balance between osteoblast and osteoclast activity guarantees optimal bone formation and resorption, pathological conditions affecting the bone may arise. In recent years, emerging evidence has shown that epigenetic mechanisms play an important role during osteoblastogenesis and osteoclastogenesis processes, including long non-coding RNAs (lncRNAs). These molecules are a class of ncRNAs with lengths exceeding 200 nucleotides not translated into protein, that have attracted the attention of the scientific community as potential biomarkers to use for the future development of novel diagnostic and therapeutic approaches for several pathologies, including bone diseases. This review aims to provide an overview of the lncRNAs and their possible molecular mechanisms in the osteoblastogenesis and osteoclastogenesis processes. The deregulation of their expression profiles in common diseases associated with an altered bone turnover is also described. In perspective, lncRNAs could be considered potential innovative molecular biomarkers to help with earlier diagnosis of bone metabolism-related disorders and for the development of new therapeutic strategies.     

Ionizing Radiation Activates Mitochondrial Function in Osteoclasts and Causes Bone Loss in Young Adult Male Mice

The damaging effects of ionizing radiation (IR) on bone mass are well-documented in mice and humans and are most likely due to increased osteoclast number and function. However, the mechanisms leading to inappropriate increases in osteoclastic bone resorption are only partially understood. Here, we show that exposure to multiple fractions of low-doses (10 fractions of 0.4 Gy total body irradiation [TBI]/week, i.e., fractionated exposure) and/or a single exposure to the same total dose of 4 Gy TBI causes a decrease in trabecular, but not cortical, bone mass in young adult male mice. This damaging effect was associated with highly activated bone resorption. Both osteoclast differentiation and maturation increased in cultures of bone marrow-derived macrophages from mice exposed to either fractionated or singular TBI. IR also increased the expression and enzymatic activity of mitochondrial deacetylase Sirtuin-3 (Sirt3)—an essential protein for osteoclast mitochondrial activity and bone resorption in the development of osteoporosis. Osteoclast progenitors lacking Sirt3 exposed to IR exhibited impaired resorptive activity. Taken together, targeting impairment of osteoclast mitochondrial activity could be a novel therapeutic strategy for IR-induced bone loss, and Sirt3 is likely a major mediator of this effect.     

The Effect of a Sustained High-Fat Diet on the Metabolism of White and Brown Adipose Tissue and Its Impact on Insulin Resistance: A Selected Time Point Cross-Sectional Study

(1) Background: studies on the long-term dynamic changes in fat depot metabolism in response to a high-fat diet (HFD) on hepatic lipid deposition and insulin resistance are sparse. This study investigated the dynamic changes produced by HFD and the production of dysfunctional fat depots on insulin resistance and liver lipid metabolism. (2) Methods: mice fed a chow or HFD (45% kcal fat) diet had three fat depots, liver, and blood collected at 6, 10, 20, and 30 weeks. Anthropometric changes and gene markers for adipogenesis, thermogenesis, ECM remodeling, inflammation, and tissue insulin resistance were measured. (3) Results: early responses to the HFD were increased body weight, minor deposition of lipid in liver, increased adipocyte size, and adipogenesis. Later changes were dysfunctional adipose depots, increased liver fat, insulin resistance (shown by changes in ITT) accompanied by increased inflammatory markers, increased fibrosis (fibrosis > 2-fold, p < 0.05 from week 6), and the presence of crown cells in white fat depots. Later, changes did not increase thermogenic markers in response to the increased calories and decreased UCP1 and PRDM16 proteins in WAT. (4) Conclusions: HFD feeding initially increased adipocyte diameter and number, but later changes caused adipose depots to become dysfunctional, restricting adipose tissue expansion, changing the brown/beige ratios in adipose depots, and causing ectopic lipid deposition and insulin resistance.     

Prolonged Chronic Consumption of a High Fat with Sucrose Diet Alters the Morphology of the Small Intestine

(1) The high-fat diet (HFD) of western countries has dramatic effect on the health of several organs, including the digestive tract, leading to the accumulation of fats that can also trigger a chronic inflammatory process, such as that which occurs in non-alcohol steatohepatitis. The effects of a HFD on the small intestine, the organ involved in the absorption of this class of nutrients, are still poorly investigated. (2) To address this aspect, we administered a combined HFD with sucrose (HFD w/Suc, fat: 58% Kcal) regimen (18 months) to mice and investigated the morphological and molecular changes that occurred in the wall of proximal tract of the small intestine compared to the intestine of mice fed with a standard diet (SD) (fat: 18% Kcal). (3) We found an accumulation of lipid droplets in the mucosa of HFD w/Suc-fed mice that led to a disarrangement of mucosa architecture. Furthermore, we assessed the expression of several key players involved in lipid metabolism and inflammation, such as perilipin, leptin, leptin receptor, PI3K, p-mTOR, p-Akt, and TNF-α. All these molecules were increased in HFD mice compared to the SD group. We also evaluated anti-inflammatory molecules like adiponectin, adiponectin receptor, and PPAR-γ, and observed their significant reduction in the HFD w/Suc group compared to the control. Our data are in line with the knowledge that improper eating habits present a primary harmful assault on the bowel and the entire body’s health. (4) These results represent a promising starting point for future studies, helping to better understand the complex and not fully elucidated spectrum of intestinal alterations induced by the overconsumption of fat.     

Alpha-Lipoic Acid Alleviates Acute Inflammation and Promotes Lipid Mobilization During the Inflammatory Response in White Adipose Tissue of Mice

Recently, white adipose tissue has been shown to exhibit immunological activity, and may play an important role in host defense and protection against bacterial infection. Αlpha‐lipoic acid (α‐LA) has been demonstrated to function as an anti‐inflammatory and anti‐oxidant agent. However, its influence on the inflammatory response and metabolic changes in white adipose tissue remains unknown. We used male C57BL/6 mice as models to study the effect of α‐LA on the inflammatory response and metabolic changes in white adipose tissue after stimulation with lipopolysaccharide (LPS). The non‐esterified fatty acid content was measured by an automatic biochemical analyzer. The expression of inflammation‐, lipid‐ and energy metabolism‐related genes and proteins was determined by quantitative real‐time polymerase chain reaction and western blotting. The results indicated that α‐LA significantly decreased the epididymis fat weight index and the non‐esterified fatty acid content in plasma compared with the control group. LPS significantly increased the expression of inflammation genes and α‐LA reduced their expression. The LPS‐induced expression of nuclear factor‐κB protein was decreased by α‐LA. Regarding lipid metabolism, α‐LA significantly counteracted the inhibitory effects of LPS on the expression of hormone‐sensitive lipase gene and protein. α‐LA evidently increased the gene expression of fatty acid transport protein 1 and cluster of differentiation 36. Regarding energy metabolism, α‐LA significantly increased the expression of most of mitochondrial DNA‐encoded genes compared with the control and LPS group. Accordingly, α‐LA can alleviate acute inflammatory response and this action may be related with the promotion of lipid mobilization in white adipose tissue.     

The Effects of Exercise and Activity-Based Physical Therapy on Bone after Spinal Cord Injury

Spinal cord injury (SCI) produces paralysis and a unique form of neurogenic disuse osteoporosis that dramatically increases fracture risk at the distal femur and proximal tibia. This bone loss is driven by heightened bone resorption and near-absent bone formation during the acute post-SCI recovery phase and by a more traditional high-turnover osteopenia that emerges more chronically, which is likely influenced by the continual neural impairment and musculoskeletal unloading. These observations have stimulated interest in specialized exercise or activity-based physical therapy (ABPT) modalities (e.g., neuromuscular or functional electrical stimulation cycling, rowing, or resistance training, as well as other standing, walking, or partial weight-bearing interventions) that reload the paralyzed limbs and promote muscle recovery and use-dependent neuroplasticity. However, only sparse and relatively inconsistent evidence supports the ability of these physical rehabilitation regimens to influence bone metabolism or to increase bone mineral density (BMD) at the most fracture-prone sites in persons with severe SCI. This review discusses the pathophysiology and cellular/molecular mechanisms that influence bone loss after SCI, describes studies evaluating bone turnover and BMD responses to ABPTs during acute versus chronic SCI, identifies factors that may impact the bone responses to ABPT, and provides recommendations to optimize ABPTs for bone recovery.