Lipid Storage In Adipose Tissue Research Articles

Adipose Tissue Plasticity: A Comprehensive Definition and Multidimensional Insight.

Adipose tissue is composed of adipocytes, stromal vascular fraction, nerves, surrounding immune cells, and the extracellular matrix. Under various physiological or pathological conditions, adipose tissue shifts cellular composition, lipid storage, and organelle dynamics to respond to the stress; this remodeling is called "adipose tissue plasticity". Adipose tissue plasticity includes changes in the size, species, number, lipid storage capacity, and differentiation function of adipocytes, as well as alterations in the distribution and cellular composition of adipose tissue. This plasticity has a major role in growth, obesity, organismal protection, and internal environmental homeostasis. Moreover, certain thresholds exist for this plasticity with significant individualized differences. Here, we comprehensively elaborate on the specific connotation of adipose tissue plasticity and the relationship between this plasticity and the development of many diseases. Meanwhile, we summarize possible strategies for treating obesity in response to adipose tissue plasticity, intending to provide new insights into the dynamic changes in adipose tissue and contribute new ideas to relevant clinical problems.

Downregulation of adipose LPL by PAR2 contributes to the development of hypertriglyceridemia.

Lipoprotein lipase (LPL) hydrolyzes circulating triglycerides (TGs), releasing fatty acids (FA) and promoting lipid storage in white adipose tissue (WAT). However, the mechanisms regulating adipose LPL and its relationship with the development of hypertriglyceridemia are largely unknown. WAT from obese humans exhibited high PAR2 expression, which was inversely correlated with the LPL gene. Decreased LPL expression was also inversely correlated with elevated plasma TG levels, suggesting that adipose PAR2 might regulate hypertriglyceridemia by downregulating LPL. In mice, aging and high palmitic acid diet (PD) increased PAR2 expression in WAT, which was associated with a high level of macrophage migration inhibitory factor (MIF). MIF downregulated LPL expression and activity in adipocytes by binding with CXCR2/4 receptors and inhibiting Akt phosphorylation. In a MIF overexpression model, high-circulating MIF levels suppressed adipose LPL, and this suppression was associated with increased plasma TGs but not FA. Following PD feeding, adipose LPL expression and activity were significantly reduced, and this reduction was reversed in Par2-/- mice. Recombinant MIF infusion restored high plasma MIF levels in Par2-/- mice, and the levels decreased LPL and attenuated adipocyte lipid storage, leading to hypertriglyceridemia. These data collectively suggest that downregulation of adipose LPL by PAR2/MIF may contribute to the development of hypertriglyceridemia.

Single-cell Analysis of Subcutaneous Fat Reveals Pro-fibrotic Cells that Correlate with Visceral Adiposity in HIV.

Cardiometabolic diseases are common in persons with HIV (PWH) on antiretroviral therapy (ART), which has been attributed to preferential lipid storage in visceral adipose tissue (VAT) compared with subcutaneous adipose tissue (SAT). However, the relationship of SAT-specific cellular and molecular programs with VAT volume is poorly understood in PWH. We characterized SAT cell-type specific composition and transcriptional programs that are associated with greater VAT volume in PWH on contemporary ART. We enrolled PWH on long-term ART with a spectrum of metabolic health. Ninety-two participants underwent SAT biopsy for bulk RNA sequencing and 43 had single-cell RNA sequencing. Computed tomography quantified VAT volume and insulin resistance was calculated using HOMA2-IR. VAT volume was associated with HOMA2-IR (p < 0.001). Higher proportions of SAT intermediate macrophages (IMs), myofibroblasts, and MYOC + fibroblasts were associated with greater VAT volume using partial Spearman's correlation adjusting for age, sex, and body mass index (ρ=0.34-0.49, p < 0.05 for all). Whole SAT transcriptomics showed PWH with greater VAT volume have increased expression of extracellular matrix (ECM)- and inflammation-associated genes, and reduced expression of lipolysis- and fatty acid metabolism-associated genes. In PWH, greater VAT volume is associated with higher proportion of SAT IMs and fibroblasts, and a SAT ECM and inflammatory transcriptome, which is similar to findings in HIV-negative persons with obesity. These data identify SAT cell-type specific changes associated with VAT volume in PWH that could underlie the high rates of cardiometabolic diseases in PWH, though additional longitudinal studies are needed to define directionality and mechanisms.

Myoglobin: A versatile age-old oxygen carrying hemoprotein and its emerging role in metabolite regulation in diverse tissues

Myoglobin (Mb) is an age-old heme containing cytoplasmic protein primarily expressed in heart and skeletal muscles, which is capable of rapid release of O2 during the periods of hypoxia or anoxia. The canonical view of the primary physiological function of Mb is that it is a tissue oxygen (O2) storage protein supporting mitochondrial oxidative phosphorylation especially as the tissue O2 partial pressure ( pO2) drops and Mb increasingly offloads O2. For the past 50 years, many investigators are constantly exploring wide-range of physiological functions and metabolic regulation activities of Mb. Advanced genetic engineering tools and molecular techniques revealed important new insights and provided additional functions of Mb. However, accumulating evidence indicates that this paradigm is too narrow, especially in light of recent findings supporting plausible functions for Mb in lipid traffcking and sequestration, binding of small molecules such as lactate (LAC), pyruvate (PYR), glucose (GLU), polyamines, and glutathione (GSH), and “ectopic” expression in some types of cancer cells. Data from Mb knockout mice (Mb−/−) and biochemical models suggest additional metabolic roles for Mb, especially regulation of nitric oxide (NO) pools and modulation of thermogenic brown adipose tissue (BAT) bioenergetics and lipid storage phenotypes. From these and other findings in the literature over many decades, it may be contemplated that the primary role for Mb under most conditions for Mb besides delivering O2 in support of oxidative phosphorylation, but also serve as an O2-sensor that modulates intracellular O2- and NO-responsive molecular signaling pathways. This paradigm shift reflect a fundamental change in how oxidative metabolism and cell regulation are viewed in Mb-expressing cells such as skeletal muscle, heart, brown adipocytes, and select cancer cells. Herein, we present historic and emerging views related to the physiological roles for Mb, and working models illustrating the possible importance of interactions between Mb, gases, and small molecule metabolites in regulation of cell signaling and bioenergetics. USDA-ARS project 6026-51000-010-06S, Sturgis Foundation Grant AWD00054750 and ACRI-ABI Investigator Initiated Grant Award GR037175-4450S ABI. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hippo–YAP/TAZ signalling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass

Adipose tissues serve as an energy reservoir and endocrine organ, yet the mechanisms that coordinate these functions remain elusive. Here, we show that the transcriptional coregulators, YAP and TAZ, uncouple fat mass from leptin levels and regulate adipocyte plasticity to maintain metabolic homeostasis. Activating YAP/TAZ signalling in adipocytes by deletion of the upstream regulators Lats1 and Lats2 results in a profound reduction in fat mass by converting mature adipocytes into delipidated progenitor-like cells, but does not cause lipodystrophy-related metabolic dysfunction, due to a paradoxical increase in circulating leptin levels. Mechanistically, we demonstrate that YAP/TAZ–TEAD signalling upregulates leptin expression by directly binding to an upstream enhancer site of the leptin gene. We further show that YAP/TAZ activity is associated with, and functionally required for, leptin regulation during fasting and refeeding. These results suggest that adipocyte Hippo–YAP/TAZ signalling constitutes a nexus for coordinating adipose tissue lipid storage capacity and systemic energy balance through the regulation of adipocyte plasticity and leptin gene transcription.

Autophagic Regulation of Adipogenesis Through TP53INP2: Insights from In Silico and In Vitro Analysis.

Obesity is an epidemic disease associated with multimorbidity resulting in higher mortality risk. The imbalance between energy storage and expenditure is the prime factor in the prognosis of the disease. Specifically, excessive lipid storage through adipogenesis leads to obesity. Adipogenesis is the process that converts preadipocytes into mature adipocytes by regulating major transcription factors like PPARγ and C/EBPα, contributes to lipid storage in adipose tissue. On the contrary, autophagy is a self-degradative process that maintains homeostasis in adipose tissue by regulating adipogenesis and lipolysis. TP53INP2 is a key player that regulates the autophagy process, and it negatively regulates adipogenesis and lipid storage. The gene expression profile GSE93637 was retrieved from the GEO database and analyzed using an integrated bioinformatics approach. The differentially expressed genes (DEGs) were analyzed using R-Bioconductor for TP53INP2 knockdown microarray dataset of 3T3L1 cells, and the DEGs were analyzed for the functional enrichment analysis. Further, the genes involved in the potential biological and molecular functions were evaluated for pathway enrichment analysis by KEGG (Kyoto Encyclopedia of Genes and Genomes). A total of 726 DEGs were found including 391 upregulated and 335 downregulated genes. Further, the functional and pathway enrichment analysis was employed to identify the highly interacting genes, and we identified a total of 56 genes that are highly interacting through a protein-protein interaction network. The DEGs mainly regulate the Peroxisome proliferator-activated receptor (PPAR) signaling pathway, lipolysis, and autophagy. Further, we investigated the associated Hub genes for enriched pathway genes and found the involvement of two autophagic genes ATG7 and sequestosome 1 (p62). In addition, in vitro studies of qRT-PCR (Quantitative real-time polymerase chain reaction) and Western blot analysis revealed that increased autophagy resulted in reduced lipid storage through down-regulation of the adipogenic gene. Moreover, increased expression of autophagic gene TP53INP2 and ATG7 facilitates the down-regulation of p62 and PPARγ gene resulting in lipolysis in mature adipocytes through autophagy. There is no specific treatment to reduce obesity other than a caloric diet and exercise. Hence, this study provides sufficient evidence to conclude that TP53INP2 negatively regulates adipogenesis and increases the degradation of lipids in mature adipocytes which is crucial for reducing obesity. Therefore, it is plausible to consider TP53INP2 as a promising therapeutic target for managing adipogenesis and obesity. However, further studies are necessary to validate their functional and molecular pathway analysis in the regulation of adipogenesis and obesity.

Proteomic analysis reveals semaglutide impacts lipogenic protein expression in epididymal adipose tissue of obese mice.

Obesity is a global health problem with few pharmacologic options. Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that induces weight loss. Yet, the role of semaglutide in adipose tissue has not yet been examined. The following study investigated the mechanism of semaglutide on lipid metabolism by analyzing proteomics of epididymal white adipose tissue (eWAT) in obese mice. A total of 36 C57BL/6JC mice were randomly divided into a normal-chow diet group (NCD, n = 12), high-fat diet (HFD, n = 12), and HFD+semaglutide group (Sema, n = 12). Mice in the Sema group were intraperitoneally administered semaglutide, and the HFD group and the NCD group were intraperitoneally administered an equal volume of normal saline. Serum samples were collected to detect fasting blood glucose and blood lipids. The Intraperitoneal glucose tolerance test (IPGTT) was used to measure the blood glucose value at each time point and calculate the area under the glucose curve. Tandem Mass Tag (TMT) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to study the expression of eWAT, while cellular processes, biological processes, corresponding molecular functions, and related network molecular mechanisms were analyzed by bioinformatics. Compared with the model group, the semaglutide-treated mice presented 640 differentially expressed proteins (DEPs), including 292 up-regulated and 348 down-regulated proteins. Bioinformatics analysis showed a reduction of CD36, FABP5, ACSL, ACOX3, PLIN2, ANGPTL4, LPL, MGLL, AQP7, and PDK4 involved in the lipid metabolism in the Sema group accompanied by a decrease in visceral fat accumulation, blood lipids, and improvement in glucose intolerance. Semaglutide can effectively reduce visceral fat and blood lipids and improve glucose metabolism in obese mice. Semaglutide treatment might have beneficial effects on adipose tissues through the regulation of lipid uptake, lipid storage, and lipolysis in white adipose tissue.

Differential Strain-dependent Ovarian and Metabolic Responses in a Mouse Model of PCOS.

Several mouse models have been developed to study polycystic ovarian syndrome (PCOS), a leading cause of infertility in women. Treatment of mice with DHT for 90 days causes ovarian and metabolic phenotypes similar to women with PCOS. We used this 90-day DHT treatment paradigm to investigate the variable incidence and heterogeneity in 2 inbred mouse strains, NOD/ShiLtJ and 129S1/SvlmJ. NOD mice naturally develop type 1 diabetes, and recent meta-analysis found increased androgen excess and PCOS in women with type 1 diabetes. The 129S1 mice are commonly used in genetic manipulations. Both NOD and 129S1 DHT-treated mice had early vaginal opening, increased anogenital distance, and altered estrus cycles compared with control animals. Additionally, both NOD and 129S1 mice had reduced numbers of corpora lutea after DHT exposure, whereas NOD mice had decreased numbers of preantral follicles and 129S1 mice had reduced numbers of small antral follicles. NOD mice had increased body weight, decreased white adipocyte size, and improved glucose sensitivity in response to DHT, whereas 129S1 mice had increased body weight and white adipocyte size. NOD mice had increased expression of Adiponectin, Cidea, Srebp1a, and Srebp1b and 129S1 mice had decreased Pparg in the white adipose tissues, whereas both NOD and 129S1 mice had increased expression of Glut4 and Prdm16, suggesting DHT may differentially affect glucose transport, thermogenesis, and lipid storage in white adipose tissue. DHT causes different ovarian and metabolic responses in NOD and 129S1 mice, suggesting that strain differences may allow further elucidation of genetic contributions to PCOS.

An obesogenic diet uncovers disparate changes in uncoupling protein 1 content and lipid synthesis and storage in rat brown adipose tissue.

An obesogenic diet uncovers disparate changes in uncoupling protein 1 content and lipid synthesis and storage in rat brown adipose tissue.

IDF21-0482 Hepatokine, Angiopoietin-like proteins 8 (ANGPTL8) in omental adipose tissue is positively associated with BMI

Background: Obesity defined as abnormal or excessive fat accumulation that presents major risk factors for several chronic diseases, including diabetes, cardiovascular diseases and cancer. Obesity now becomes a disease that required medical involvement. BMI has been used as a tool for the diagnosis obesity, however, some important limitations of BMI were known in individuals with normal BMI but have excessive percentage of body fatness while being labeled as non-obese subject. Therefore, in addition to BMI, more obesity-related factors or biomarkers are needed as criteria for diagnosis. Angiopoietin-like proteins 8 (ANGPTL8) is a member in the ANGPTL family and as regulator in lipid metabolism. It also plays the role in beta-cell proliferation, expansion and islet function. Serum levels of ANGPTL8 in humans were correlated with improved adipose tissue lipid storage and lower serum triglyceride levels in the fed state. But it is still unclear about correlation between expression levels of ANGPTL8 in different parts of adipose tissues and metabolic parameters. The more specific mechanisms for the regulation of ANGPTL8 on lipid and glucose metabolism still need for more investigation. Our study recruited 330 human subjects, including 281 obesity subjects and 49 non-obesity subjects. We collected the residual specimens from bariatric surgery and intra-abdominal surgery, all the participants had signed informed consent before enrolment. In this study, we found out that the ANGPTL8 level in omental adipose tissue is positively correlated with BMI. We also demonstrated that ANGPTL8 expression is significantly higher in the late stage of adipocytes differentiation than that in the early stage of adipocytes differentiation. Consistently, ANGPTL8 expression in omental adipose tissue is significantly higher in mice fed with high fat/high sucrose diet than that in normal chow diet. As our knowledge, this is the first study to demonstrate the positive association of ANGPTL8 expression in specific depot of adipose tissue with BMI and validated in both cellular and animal model of obesity. The finding indicated ANGPTL8 may be a potential biomarker of obesity.

Effects of SGLT2 inhibition on lipid transport in adipose tissue in type 2 diabetes.

SGLT2 inhibition induces an insulin-independent reduction in plasma glucose causing increased lipolysis and subsequent lipid oxidation by energy-consuming tissues. However, it is unknown whether SGLT2 inhibition also affects lipid storage in adipose tissue. Therefore, we aimed to determine the effects of SGLT2 inhibition on lipid storage and lipolysis in adipose tissue. We performed a randomized, double-blinded, placebo-controlled crossover design of 4 weeks of empagliflozin 25 mg and placebo once-daily in 13 individuals with type 2 diabetes treated with metformin. Adipose tissue fatty acid uptake, lipolysis rate and clearance were measured by 11C-palmitate PET/CT. Adipose tissue glucose uptake was measured by 18F-FDG PET/CT. Protein and gene expression of pathways involved in lipid storage and lipolysis were measured in biopsies of abdominal s.c. adipose tissue. Subjects were weight stable, which allowed us to quantify the weight loss-independent effects of SGLT2 inhibition. We found that SGLT2 inhibition did not affect free fatty acids (FFA) uptake in abdominal s.c. adipose tissue but increased FFA uptake in visceral adipose tissue by 27% (P < 0.05). In addition, SGLT2 inhibition reduced GLUT4 protein (P = 0.03) and mRNA content (P = 0.01) in abdominal s.c. adipose tissue but without affecting glucose uptake. In addition, SGLT2 inhibition decreased the expression of genes involved in insulin signaling in adipose tissue. We conclude that SGLT2 inhibition reduces GLUT4 gene and protein expression in abdominal s.c. adipose tissue, which could indicate a rebalancing of substrate utilization away from glucose oxidation and lipid storage capacity through reduced glycerol formation.

The Oleaginous Conglomerate- Multiple Symmetric Lipomatosis

Multiple symmetric lipomatosis (MSL) is an exceptional disorder of adipose tissue metabolism and lipid storage. The condition was initially scripted by Sir Benjamin Brodie in 1846 and is additionally designated as Made lung’s disease, Launois-Bensaude syndrome or benign symmetric lipomatosis (1). Characteristically, multiple symmetric lipomatosis displays multiple foci of accumulated, non-encapsulated, mature adipose tissue with predominant infiltration within subcutaneous tissue of cephalic, cervical and upper thoracic region. Multiple, non-encapsulated, symmetrically distributed lipomas which spare distal extremities are enunciated in multiple symmetric lipomatosis (1,2). The condition can be misinterpreted as simple obesity on account of identical clinical features and symptoms. Therefore, antecedent evaluation of pertinent manifestations and differentiation of dual entities is necessitated. The disease is presumed to be a condition diverse from accumulation of brown adipose tissue. Histological structure of constituent adipose tissue cells is dystrophic with characteristics akin to lipoma and liposarcoma. The condition may be associated with significant morbidity, metabolic disturbances, neuropathy, malignant metamorphosis and sudden death (1,2).

Expression Signatures of microRNAs and Their Targeted Pathways in the Adipose Tissue of Chickens during the Transition from Embryonic to Post-Hatch Development.

As the chick transitions from embryonic to post-hatching life, its metabolism must quickly undergo a dramatic switch in its major energy source. The chick embryo derives most of its energy from the yolk, a lipid-rich/carbohydrate-poor source. Upon hatching, the chick’s metabolism must then be able to utilize a lipid-poor/carbohydrate-rich source (feed) as its main form of energy. We recently found that a number of hepatically-expressed microRNAs (miRNAs) help facilitate this shift in metabolic processes in the chick liver, the main site of lipogenesis. While adipose tissue was initially thought to mainly serve as a lipid storage site, it is now known to carry many metabolic, endocrine, and immunological functions. Therefore, it would be expected that adipose tissue is also an important factor in the metabolic switch. To that end, we used next generation sequencing (NGS) and real-time quantitative PCR (RT-qPCR) to generate miRNome and transcriptome signatures of the adipose tissue during the transition from late embryonic to early post-hatch development. As adipose tissue is well known to produce inflammatory and other immune factors, we used SPF white leghorns to generate the initial miRNome and transcriptome signatures to minimize complications from external factors (e.g., pathogenic infections) and ensure the identification of bona fide switch-associated miRNAs and transcripts. We then examined their expression signatures in the adipose tissue of broilers (Ross 708). Using E18 embryos as representative of pre-switching metabolism and D3 chicks as a representative of post-switching metabolism, we identified a group of miRNAs which work concordantly to regulate a diverse but interconnected group of developmental, immune and metabolic processes in the adipose tissue during the metabolic switch. Network mapping suggests that during the first days post-hatch, despite the consumption of feed, the chick is still heavily reliant upon adipose tissue lipid stores for energy production, and is not yet efficiently using their new energy source for de novo lipid storage. A number of core master regulatory pathways including, circadian rhythm transcriptional regulation and growth hormone (GH) signaling, likely work in concert with miRNAs to maintain an essential balance between adipogenic, lipolytic, developmental, and immunological processes in the adipose tissue during the metabolic switch.

Vehicle emissions-exposure alters expression of systemic and tissue-specific components of the renin-angiotensin system and promotes outcomes associated with cardiovascular disease and obesity in wild-type C57BL/6 male mice.

Exposure to air pollution from traffic-generated sources is known to contribute to the etiology of inflammatory diseases, including cardiovascular disease (CVD) and obesity; however, the signaling pathways involved are still under investigation. Dysregulation of the renin-angiotensin system (RAS) can contribute to CVD and alter lipid storage and inflammation in adipose tissue. Our previous exposure studies revealed that traffic-generated emissions increase RAS signaling, further exacerbated by a high-fat diet. Thus, we investigated the hypothesis that exposure to engine emissions increases systemic and local adipocyte RAS signaling, promoting the expression of factors involved in CVD and obesity. Male C57BL/6 mice (6-8 wk old) were fed either a high-fat (HF, n = 16) or low-fat (LF, n = 16) diet, beginning 30d prior to exposures, and then exposed via inhalation to either filtered air (FA, controls) or a mixture of diesel engine + gasoline engine vehicle emissions (MVE: 100 μg PM/m3) via whole-body inhalation for 6 h/d, 7 d/wk, 30d. Endpoints were assessed via immunofluorescence and RT-qPCR. MVE-exposure promoted vascular adhesion factors (VCAM-1, ICAM-1) expression, monocyte/macrophage sequestration, and oxidative stress in the vasculature, associated with increased angiotensin II receptor type 1 (AT1) expression. In the kidney, MVE-exposure promoted the expression of renin, AT1, and AT2 receptors. In adipose tissue, both HF-diet and MVE-exposure mediated increased epididymal fat pad weight and adipocyte hypertrophy, associated with increased angiotensinogen and AT1 receptor expression; however, these outcomes were further exacerbated in the MVE + HF group. MVE-exposure also induced inflammation, monocyte chemoattractant protein (MCP)-1, and leptin, while reducing insulin receptor and glucose transporter, GLUT4, expression in adipose tissue. Our results indicate that MVE-exposure promotes systemic and local adipose RAS signaling, associated with increased expression of factors contributing to CVD and obesity, further exacerbated by HF diet consumption.

Plasma glutamate metabolism correlates with cognitive function and the brain‐adipose axis in a presymptomatic Alzheimer’s cohort

AbstractBackgroundIn addition to the amyloid hypothesis, it is accepted that neurotransmitter and energy dyshomeostasis may underlie AD pathology. Glutamate (Glu) is one of the most common excitatory neurotransmitters and is the precursor of glutamine (Gln) and pyroglutamine (PGln). Glu signaling intersects with lipid metabolism via neuronal phospholipase A2 activation and the regulation of adiposity. Lipids are a major storage form of energy that is critical to AD pathology. We propose that disturbance in Glu metabolism may interfere with how the brain regulates lipid storage in adipose tissue and its utilization by tissues, and this process can contribute to early AD pathology. Consequently, the aim of our study is to quantify plasma Glu and its metabolites and determine their interaction with lipid metabolism in a pre‐symptomatic AD cohort.MethodsWe collected fasting blood samples from cognitively healthy (CH) study participants with normal cerebrospinal fluid amyloid/ tau ratio (CH‐NAT, n = 36) or with pathological amyloid/tau ratio (CH‐PAT, n = 34), and from AD participants (n = 26). The concentrations of Glu, Gln, and PGln were measured using liquid chromatography‐tandem mass spectrometry. Blood lipids were measured in a clinical laboratory (HMH, Pasadena) and CSF measures of Aβ42 and total tau were determined using an ELISA.ResultsBlood plasma Glu but not Gln and PGln positively correlated with CSF Aβ42/T‐tau ratio, in CH and CH‐NAT (p = 0.02) but not in CH‐PAT (p &gt; 0.05) or AD (p = 0.99) participants. Blood plasma Glu also positively correlated with mean diastolic pressure (p = 0.02), BMI (p = 0.001), plasma triglycerides (p &lt; 0.0001), and VLDL‐cholesterol (p &lt; 0.0001), and negatively correlated with HDL‐cholesterol (p = 0.0003), in all CH study participants. Glu did not correlate with BMI but correlated strongly with VLDL‐cholesterol in CH‐NAT. In contrast, Glu correlated with BMI but not with VLDL‐cholesterol in CH‐PAT.ConclusionsThese data show the differential regulation of blood glutamate metabolism, CSF amyloid/tau, and plasma lipids in pre‐symptomatic AD compared with cognitively healthy participants. We propose that glutamate metabolism and the brain‐adipose interface may be involved in regulating cognitive function and improving its homeostasis may prevent the decline from cognitively healthy to pre‐symptomatic or AD pathology in elderly populations.

Drosophila PDGF/VEGF signaling from muscles to hepatocyte-like cells protects against obesity.

PDGF/VEGF ligands regulate a plethora of biological processes in multicellular organisms via autocrine, paracrine, and endocrine mechanisms. We investigated organ-specific metabolic roles of Drosophila PDGF/VEGF-like factors (Pvfs). We combine genetic approaches and single-nuclei sequencing to demonstrate that muscle-derived Pvf1 signals to the Drosophila hepatocyte-like cells/oenocytes to suppress lipid synthesis by activating the Pi3K/Akt1/TOR signaling cascade in the oenocytes. Functionally, this signaling axis regulates expansion of adipose tissue lipid stores in newly eclosed flies. Flies emerge after pupation with limited adipose tissue lipid stores and lipid level is progressively accumulated via lipid synthesis. We find that adult muscle-specific expression of pvf1 increases rapidly during this stage and that muscle-to-oenocyte Pvf1 signaling inhibits expansion of adipose tissue lipid stores as the process reaches completion. Our findings provide the first evidence in a metazoan of a PDGF/VEGF ligand acting as a myokine that regulates systemic lipid homeostasis by activating TOR in hepatocyte-like cells.

Adaptive Fat Oxidation Is Coupled with Increased Lipid Storage in Adipose Tissue of Female Mice Fed High Dietary Fat and Sucrose.

Western diets high in fat and sucrose are associated with metabolic syndrome (MetS). Although the prevalence of MetS in women is comparable to that in men, metabolic adaptations in females to Western diet have not been reported in preclinical studies. This study investigates the effects of Western diet on risk factors for MetS in female mice. Based on our earlier studies in male mice, we hypothesized that dietary supplementation with extracts of Artemisia dracunculus L. (PMI5011) and Momordica charantia (bitter melon) could affect MetS risk factors in females. Eight-week-old female mice were fed a 10% kcal fat, 17% kcal sucrose diet (LFD); high-fat, high-sucrose diet (HFS; 45% kcal fat, 30% kcal sucrose); or HFS diet with PMI5011 or bitter melon for three months. Body weight and adiposity in all HFS groups were greater than the LFD. Total cholesterol level was elevated with the HFS diets along with LDL cholesterol, but triglycerides and free fatty acids were unchanged from the LFD. Over the three month period, female mice responded to the HFS diet by adaptive increases in fat oxidation energy in muscle and liver. This was coupled with increased fat storage in white and brown adipose tissue depots. These responses were enhanced with botanical supplementation and confer protection from ectopic lipid accumulation associated with MetS in female mice fed an HFS diet.

Circulating and Adipose Tissue Fatty Acid Composition in Black South African Women with Obesity: A Cross-Sectional Study.

Background and Aims: During positive energy balance, excess lipid storage in subcutaneous adipose tissue (SAT) is associated with increased lipolysis. Elevated circulating fatty acid (FA) concentrations from both SAT lipolysis and dietary fat intake may result in visceral adipose tissue (VAT) accumulation, impairment of glucose metabolism, altogether increasing obesity-associated metabolic risks. We aimed to test the hypothesis that FA composition of red blood cell total phospholipids (RBC-TPL) and SAT is associated with body fat centralisation (VAT/SAT ratio) and insulin sensitivity (SI) in black South African women with obesity. Methods: Participants’ (n = 41) body fat composition and distribution, SI, and RBC-TPL, abdominal and gluteal SAT (gSAT) FA composition (gas-liquid chromatography) were measured. Results: RBC-TPL contained higher proportions of saturated fatty acids (SFAs) than SAT (p < 0.001), which were associated with lower SI (p < 0.05). Mono-unsaturated fatty acids (MUFAs) and stearoyl-CoA desaturase-1 (SCD1)-16 were lower, while poly-unsaturated fatty acids (PUFAs), and delta-5 and delta-6 desaturase indices were higher in RBC-TPL than SAT (p < 0.001). Interestingly, FA profiles differed between SAT depots with higher SFAs and lower MUFAs, SCD1-16 and SCD1-18 indices in abdominal compared to gluteal SAT (p < 0.01). In both SAT depots, higher SFAs and lower PUFAs (n-3 and n-6) correlated with lower VAT/SAT ratio; and lower PUFAs (n-3 and n-6) and higher total MUFA correlated with higher SI. Conclusion: Our findings confirm the relationships between the FA composition of RBC-TPL and SAT and metabolic risk in black women with obesity, which are dependent on both the FA class, and the tissue type/blood compartment in which they are distributed.

Nanoformulated SOD1 ameliorates the combined NASH and alcohol-associated liver disease partly via regulating CYP2E1 expression in adipose tissue and liver

Enhanced free fatty acid (FFA) flux from adipose tissue (AT) to liver plays an important role in the development of nonalcoholic steatohepatitis (NASH) and alcohol-associated liver disease (AALD). We determined the effectiveness of nanoformulated superoxide dismutase 1 (Nano) in attenuating liver injury in a mouse model exhibiting a combination of NASH and AALD. Male C57BL6/J mice were fed a chow diet (CD) or a high-fat diet (HF) for 10 wk followed by pair feeding of the Lieber-DeCarli control (control) or ethanol (ET) diet for 4 wk. Nano was administered once every other day for the last 2 wk of ET feeding. Mice were divided into 1) CD + control diet (CD + Cont), 2) high-fat diet (HF) + control diet (HF + Cont), 3) HF + Cont + Nano, 4) HF + ET diet (HF + ET), and 5) HF + ET + Nano. The total fat mass, visceral AT mass (VAT), and VAT perilipin 1 content were significantly lower only in HF + ET-fed mice but not in HF + ET + Nano-treated mice compared with controls. The HF + ET-fed mice showed an upregulation of VAT CYP2E1 protein, and Nano abrogated this effect. We noted a significant rise in plasma FFAs, ALT, and monocyte chemoattractant protein-1 in HF + ET-fed mice, which was blunted in HF + ET + Nano-treated mice. HF + ET-induced increases in hepatic steatosis and inflammatory markers were attenuated upon Nano treatment. Nano reduced hepatic CYP2E1 and enhanced catalase levels in HF + ET-fed mice with a concomitant increase in SOD1 protein and activity in liver. Nano was effective in attenuating AT and liver injury in mice exhibiting a combination of NASH and AALD, partly via reduced CYP2E1-mediated ET metabolism in these organs.NEW & NOTEWORTHY Increased free fatty acid flux from adipose tissue (AT) to liver accompanied by oxidative stress promotes nonalcoholic steatohepatitis (NASH) and alcohol-associated liver injury (AALD). Obesity increases the severity of AALD. Using a two-hit model involving a high-fat diet and chronic ethanol feeding to mice, and treating them with nanoformulated superoxide dismutase (nanoSOD), we have shown that nanoSOD improves AT lipid storage, reduces CYP2E1 in AT and liver, and attenuates the combined NASH/AALD in mice.

Diverse repertoire of human adipocyte subtypes develops from transcriptionally distinct mesenchymal progenitor cells

Single-cell sequencing technologies have revealed an unexpectedly broad repertoire of cells required to mediate complex functions in multicellular organisms. Despite the multiple roles of adipose tissue in maintaining systemic metabolic homeostasis, adipocytes are thought to be largely homogenous with only 2 major subtypes recognized in humans so far. Here we report the existence and characteristics of 4 distinct human adipocyte subtypes, and of their respective mesenchymal progenitors. The phenotypes of these distinct adipocyte subtypes are differentially associated with key adipose tissue functions, including thermogenesis, lipid storage, and adipokine secretion. The transcriptomic signature of "brite/beige" thermogenic adipocytes reveals mechanisms for iron accumulation and protection from oxidative stress, necessary for mitochondrial biogenesis and respiration upon activation. Importantly, this signature is enriched in human supraclavicular adipose tissue, confirming that these cells comprise thermogenic depots in vivo, and explain previous findings of a rate-limiting role of iron in adipose tissue browning. The mesenchymal progenitors that give rise to beige/brite adipocytes express a unique set of cytokines and transcriptional regulators involved in immune cell modulation of adipose tissue browning. Unexpectedly, we also find adipocyte subtypes specialized for high-level expression of the adipokines adiponectin or leptin, associated with distinct transcription factors previously implicated in adipocyte differentiation. The finding of a broad adipocyte repertoire derived from a distinct set of mesenchymal progenitors, and of the transcriptional regulators that can control their development, provides a framework for understanding human adipose tissue function and role in metabolic disease.