Loss Of Adipose Tissue Research Articles

Zonated leucine sensing by Sestrin-mTORC1 in the liver controls the response to dietary leucine.

The mechanistic target of rapamycin complex 1 (mTORC1) kinase controls growth in response to nutrients, including the amino acid leucine. In cultured cells, mTORC1 senses leucine through the leucine-binding Sestrin proteins, but the physiological functions and distribution of Sestrin-mediated leucine sensing in mammals are unknown. We find that mice lacking Sestrin1 and Sestrin2 cannot inhibit mTORC1 upon dietary leucine deprivation and suffer a rapid loss of white adipose tissue (WAT) and muscle. The WAT loss is driven by aberrant mTORC1 activity and fibroblast growth factor 21 (FGF21) production in the liver. Sestrin expression in the liver lobule is zonated, accounting for zone-specific regulation of mTORC1 activity and FGF21 induction by leucine. These results establish the mammalian Sestrins as physiological leucine sensors and reveal a spatial organization to nutrient sensing by the mTORC1 pathway.

Characterization and Clinical Association of Autoantibodies Against Perilipin 1 in Patients With Acquired Generalized Lipodystrophy.

Acquired generalized lipodystrophy (AGL) is a rare condition characterized by massive loss of adipose tissue through the body, causing severe metabolic complications. Autoimmune destruction of adipocytes is strongly suspected based on the frequent association of AGL with autoimmune disorders. In 2018, autoantibodies against perilipin 1 (PLIN1) were identified in three patients with autoimmune-associated AGL. However, the pathogenic mechanism and clinical impact of anti-PLIN1 remain unsolved. The prevalence of anti-PLIN1 autoantibodies in an AGL cohort of 40 patients was 50% (20 of 40). Among positive patients, 10 had the autoimmune variety and 10 had panniculitis-associated AGL. The IgG isotype was predominant, although some IgM antibodies were detected. Epitope-mapping studies did not identify a single, major epitope. Instead, autoantibodies typically bound to several different peptides, among which the central (233-405) domain was detected in all antibody-positive patients, for both IgG and IgM autoantibodies. In-depth epitope mapping indicated that anti-PLIN1 autoantibodies predominantly recognize the αβ-hydrolase domain containing 5 (ABHD5) binding site (383-405). Autoantibodies dose-dependently blocked the binding of PLIN1 to ABHD5 and caused a dislocation of ABHD5 toward the cytosol, leading to an increase in lipolysis and lipase activities. Finally, anti-PLIN1 titers significantly correlated with the amount of fat loss, metabolic control impairment, and severity of liver injury. Our data strongly support that anti-PLIN1 autoantibodies are a diagnostic biomarker and a cause of lipodystrophy in patients with AGL.

Abstract 5818: Features of cancer cachexia in non-small cell lung cancer: Insights from the prospective TRACERx study

Abstract Introduction: Cancer cachexia (CC) is a major contributor to morbidity and mortality in patients with non-small cell lung cancer (NSCLC). It is characterized by loss of skeletal muscle (SM) tissue with or without adipose tissue loss. This analysis reports on the characteristics and outcomes of patients recruited into the prospective TRACERx study, who presented with or subsequently developed features of CC during follow-up. Approach: Using longitudinal CT imaging, total, subcutaneous and visceral adipose tissue (TAT, SAT, VAT) and SM volumes were manually quantified at the 3rd lumbar vertebrae level. Body weight was measured every 3-6 months and grouped according to BMI-adjusted weight loss grades. Multi-region primary tumour tissue was collected at the time of surgical resection and subjected to whole exome and RNA sequencing. Results: Patients in the TRACERx 421 cohort who presented with low SAT volume at diagnosis, represented by the lower 20% percentile of the cohort, had significantly shorter lung-cancer specific survival (LCSS) and overall survival (OS) compared with patients in the 80% percentile (3-y LCSS 61% vs 81%, p<0.001; 3-y OS 57% vs 69%, p=0.02). Patients presenting with low VAT had a significantly shorter LCSS (3-y-LCSS 66% vs 79%, p=0.01), but not OS (3-y OS 60% vs 69%). Low SM volume was not associated with LCSS or OS. However, loss of SM volume of ≥20% between diagnosis and disease relapse was associated with significantly reduced LCSS and OS (3-y LCSS 30% vs 49%, p=0.02; 3-y OS 26% vs 45%, p=0.03). Based on a multivariable model, low SAT volume at diagnosis and SM loss were independent prognostic factors for LCSS, but not OS. In addition, BMI-adjusted weight loss was associated with shorter OS and LCSS (3-y OS 7% for patients with weight loss grade 4 vs 54% in patients with stable weight, p<0.001 [LCSS 8% vs 61%, p<0.001]). Preliminary genomic data from patients with disease recurrence and with (n=47) or without (n=107) features of CC, defined as SAT or muscle loss >20% or weight loss grade 4, demonstrated distinct copy number alteration and differential gene expression profiles. Conclusion: In patients with early-stage NSCLC, both altered body composition and weight loss in keeping with CC was associated with poor survival outcomes. In particular, low SAT volume at diagnosis and loss of SM between diagnosis and relapse were independent prognostic factors for LCSS. Ongoing analyses in TRACERx will continue to investigate the potential tumour-intrinsic mediators of CC. Citation Format: Othman Al-Sawaf, Marcin Skrzypski, Jakob Weiss, Takahiro Karasaki, Nicolai Juul Birkbak, Francisco Zambrana, Alexander Frankell, Thomas B. Watkins, Carlos Martinez Ruiz, Selvaraju Veeriah, Cristina Naceur-Lombardelli, TRACERx Consortium, Nicholas McGranahan, Hugo Aerts, Charles Swanton, Mariam Jamal-Hanjani. Features of cancer cachexia in non-small cell lung cancer: Insights from the prospective TRACERx study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5818.

Abstract 3210: Oncostatin M modulates tumor-fibroblast crosstalk in pancreatic cancer without protecting against cachexia

Abstract Cancer cachexia is the involuntary loss of body weight, skeletal muscle, and adipose tissue associated with disease. Cachexia affects 85% of pancreatic cancer patients and patients suffer the greatest average weight loss among solid cancers. Inflammation is a key driver in cancer cachexia, specifically the Interleukin-6/GP130 family of cytokines that activate signaling of the JAK/STAT pathway. Among family members, Interleukin-6 (IL-6) and Leukemia Inhibitory Factor (LIF) promote cachexia and pancreatic cancer; however, less is known of the related Oncostatin M. Here we show cachexia and elevated circulating Osm coincide in the KrasG12D;Trp53R172H;Pdx1:Cre genetically engineered mouse model (KPC-GEMM) of pancreatic cancer and in mice bearing KPC cells implanted orthotopically. Osm expression was elevated in cardiac muscle and adipose tissue in KPC cachexia, while OSM receptor (Osmr) was elevated in cardiac and skeletal muscle and liver, indicating a systemic OSM circuit. Consistent with a feed-forward loop, KPC cells treated with OSM upregulated expression of OSMR. RNA-sequencing of OSM treated KPC and cancer-associated fibroblast (CAF) cell lines revealed activation of inflammation, fibrosis, and tumor progression pathways, including induction of IL-6. Functionally, exogenous OSM caused cardiac dysfunction, local muscle atrophy, fibrosis, and systemic bone loss in wildtype and Il6 null mice, suggesting OSM might mediate cachexia independent of IL-6. We hypothesized that deletion of OSM would be protective in cancer cachexia. Thus 14-week-old WT and Osm null mice were orthotopically implanted with KPC cells or underwent sham surgery; all groups were euthanized when one reached 5% fat mass. KPC tumors caused muscle weakness, body deconditioning and reduced activity as well as anemia and hematological inflammation. These findings were not genotype specific. There were also no differences in KPC-induced cardiac, skeletal muscle or fat wasting, nor in splenomegaly, organ wasting, or tumor size between WT and Osm null mice. Similarly, Osmr null mice showed no differences in KPC cachexia phenotypes versus wildtype mice. Nevertheless, tumors from Osm null mice showed alterations in the stromal compartment, including reduction in collagens I and III, decreased alpha smooth muscle actin staining, and altered mitochondrial metabolism and cellular composition by proteomics and RNAseq. Consistent with a role for OSM in modulating the stroma, excess OSM induced compaction of tumor cells and CAFs in 3D co-cultures. Together these data indicate that OSM signaling influences tumor-fibroblast crosstalk in the pancreatic cancer microenvironment but is not necessary for cachexia in the macroenvironment. Citation Format: Daenique H. Jengelley, Ashok Narasimhan, Joseph E. Rupert, Xiaoling Zhong, Andrew R. Young, Leonidas G. Koniaris, Teresa A. Zimmers. Oncostatin M modulates tumor-fibroblast crosstalk in pancreatic cancer without protecting against cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3210.

Abstract 2373: The RNA-binding protein HuR mediates impaired adipogenesis in pancreatic cancer cachexia

Abstract Objective: Cachexia, a wasting condition defined by chronic loss of fat and muscle, is a frequent complication of pancreatic ductal adenocarcinoma (PDAC) that negatively impacts quality of life and confers poor patient survival. Cachectic wasting cannot be abrogated by nutritional supplementation, and the mechanisms underlying this phenotype are unclear. Recent work demonstrates that human antigen R (HuR), an RNA-binding protein that regulates expression of genes involved in key cellular processes such as inflammation, stress response, and apoptosis, is also a major repressor of adipogenesis. Thus, we sought to elucidate the relative contributions of enhanced catabolism and impaired anabolism on fat wasting by investigating adipose tissue response to different nutritional contexts and HuR inhibition in cachectic mice. Methods: Adult C57BL/6J mice received orthotopic PDAC tumor injections (KrasG12D; p53R172H/+; Pdx1-cre) or sham injections. Mice were fed ad libitum, fasted 24h or fasted and refed 24h at mid-cachexia (9 days after injection). A separate cohort of PDAC mice were treated with the HuR inhibitor KH3 (100 mg/kg) at 6-, 8-, and 10-days post-injection and subjected to the same fast/refeed paradigm. Gross fat pads were weighed to assess anabolism. Adipose tissue mRNA levels were measured using RNAseq and validated with qPCR. Lipolytic rate was quantified as normalized quantity of glycerol released from inguinal (iWAT) and gonadal (gWAT) fat pads ex vivo. Results: PDAC and control mice exhibited equivalent loss of adipose tissue as a result of food restriction. Fat pads from PDAC mice displayed decreased lipolysis ex vivo and decreased lipase (Atgl & Lipe) mRNA expression. In the fast/refeed model, PDAC mice were unable to restore iWAT or gWAT mass after refeed compared to controls. RNAseq revealed 614 differentially expressed genes between gWAT from PDAC and control mice. Downregulated (n=111) genes were most closely associated with adipogenesis (adj p=5x10-3), and expression of adipogenesis master regulators Pparg and Cebpa were reduced in both iWAT and gWAT from PDAC mice. Inhibition of HuR by KH3 restored lipogenesis in refed animals with a concomitant increase in fat pad mass and associated genes regulating adipogenesis (Pparg, Cebpa, Retn, Adipoq, Fasn). Conclusion: Adipose tissue wasting during PDAC cachexia can result from impaired anabolism in the absence of excess lipolysis or malabsorption. Adipose anabolism in PDAC mice is mediated by increased HuR activity in adipocytes. Restoring anabolic potential in adipose tissue using the HuR inhibitor KH3 may provide a novel approach to alleviating PDAC cachexia. Citation Format: Beth L. Worley, Katherine Pelz, Grace McCarthy, Heike Mendez, Roberto Di Niro, Alex Chitsazan, Jonathan Brody, Aaron Grossberg. The RNA-binding protein HuR mediates impaired adipogenesis in pancreatic cancer cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2373.

Circulating Levels of MiRNAs From 320 Family in Subjects With Lipodystrophy: Disclosing Novel Signatures of the Disease.

Lipodystrophy (LD) indicates a group of rare disorders, with generalized or partial loss of white adipose tissue (WAT) often associated with metabolic derangements. Heterogeneity/wide spectrum of the disease and lack of biomarkers make diagnosis often difficult. MicroRNAs are important to maintain a correct WAT function and WAT is a source of circulating miRNAs (cmiRs). miRNAs from 320 family were previously detected in the WAT and variably associated to the metabolic syndrome. Our aim was then to investigate if LD can result in altered abundance of cmiRs-320. We collected samples from a cohort of LD subjects of various subtypes and from age matched controls. Use of quantitative PCR determined that cmiRs- 320a-3p, 320b, 320c, 320e are upregulated, while 320d is downregulated in LD. CmiRs-320 power as classifiers was more powerful in the most extreme and defined forms of LD, including the generalized and the Dunnigan subtypes. cmiR-320a-3p showed significant inverse relationships with plasma leptin (P < 0.0001), typically low in LD. The hepatic enzymes gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and the marker of inflammation C-reactive protein (CRP) were inversely related to cmiR 320d (P < 0.05, for CRP and GGT; P < 0.01, for AST and ALT). Gene ontology analysis revealed cell-cell adhesion as a process regulated by 320 miRNAs targets, thus disclosing a novel route to investigate origin of WAT loss/dysfunction. In conclusion, cmiRs-320 constitute novel biomarkers of LD, abundance of miR320a-3p is inversely associated to indicators related to WAT function, while downregulation of cmiR-320d predicts an altered hepatic profile and higher inflammation.

Paracrine Signaling From Pancreatic Ductal Cancer Cells Induced Programmed-Cell Death in 3T3-L1 Adipocytes Through Apoptosis and Ferroptosis

ObjectivesCancer cachexia is a prominent feature of patients with pancreatic ductal adenocarcinoma (PDAC). Cachexia is characterized by aberrant inflammatory responses, rapid loss of fat and muscle mass. Emerging evidence revealed that adipose tissue loss precedes muscle loss in those with cancer cachexia, suggesting that blocking cachectic fat loss is a therapeutic target. However, the underlying mechanisms by which cancer cells promote fat loss have not yet been established. We aim to investigate the molecular mechanisms behind the cachectic fat loss in PDAC patients. MethodsThe cell line derived from PDAC KPC mice (KrasG12D; Trp53R172H; Pdx1-Cre) was cultured, and conditioned-medium (CM) was collected for detecting proinflammatory cytokine levels by ELISA. An in vitro model was used to determine paracrine crosstalk between PADC and adipose tissue by transferring conditioned-medium of KPC (KPC-CM) to fully differentiated 3T3-L1 adipocytes. The effects of KPC-CM on lipolysis, lipogenesis- and iron homeostasis-related protein, proinflammatory gene expression, and signaling pathways for programmed cell death were examined. Intracellular free iron concentration and ROS production were also determined by using fluorometric assays. ResultsOur findings showed that CM of KPC cells contains various proinflammatory cytokines and chemokines associated with immune cell infiltration and oxidative stress, including CXCL1, LIX, CCL11, CCL2, IL-12, and TNFa. Addition of KPC-CM to 3T3-L1 adipocytes promoted glycerol release and phosphorylation of hormone-sensitive lipase in a dose-dependent manner, supporting augmented lipolysis. Moreover, KPC-CM reduced the adipocyte-specific gene and protein expression and promoted caspase 3-mediated apoptotic cell death. Concurrently, KPC-CM induced modification of iron metabolism, including the decreased expression of glutathione peroxidase 4 (GPX4) and increased nuclear receptor coactivator 3 (NCOA4), two biomarkers for iron-dependent programmed cell death, ferroptosis. In parallel, KPC-CM increased the intracellular Fe2+ levels and ROS production in 3T3-L1 adipocytes. ConclusionsCollectively, our results revealed that the crosstalk between adipocyte tissue and PDAC CM triggers deregulation of iron homeostasis and lipid metabolism, leading to programmed cell death of adipocytes. Funding SourcesN/A.

Piceatannol, a Dietary Polyphenol, Alleviates Adipose Tissue Loss in Pre-Clinical Model of Cancer-Associated Cachexia via Lipolysis Inhibition.

Cancer-associated cachexia (CAC) is the nutrition-independent loss of lean muscle and adipose tissues, and results in reduced chemotherapy effectiveness and increased mortality. Preventing adipose loss is considered a key target in the early stages of cachexia. Lipolysis is considered the central driver of adipose loss in CAC. We recently found that piceatannol, but not its analogue resveratrol, exhibits an inhibitory effect on lipolysis. The objective of this study was to investigate the role of piceatannol in cancer-associated lipolysis and cachexia-induced weight loss. Cancer cell-induced lipolysis in adipocytes was stimulated using cancer-conditioned media (CCM) or co-culture with human pancreatic cancer cells and the cachexia-associated cytokines TNF-α and interleukin-6 in 3T3-L1 adipocytes. C26 colon carcinoma-bearing mice were modeled using CAC in vivo. Piceatannol reduced cancer-associated lipolysis by at least 50% in both CCM and cytokine-induced lipolysis in vitro. Further gene and protein analysis confirmed that piceatannol modulated the stability of lipolytic proteins. Moreover, piceatannol protected tumor-bearing mice against weight-loss in early stages of CAC largely through preserving adipose tissue, with no effect on survival. This study demonstrates the use of a dietary compound to preserve adipose in models of early stage CAC and provides groundwork for further investigation of piceatannol or piceatannol-rich foods as alternative medicine in the preservation of body fat mass and future CAC therapy.

Impact of Early Jejunostomy Tube Feeding on Clinical Outcome and Parameters of Body Composition in Esophageal Cancer Patients Receiving Multimodal Therapy.

Malnutrition commonly affects patients with esophageal cancer and has the potential to negatively influence treatment outcomes. The aim of this study was to investigate the impact of early (preoperative) jejunostomy tube feeding (JTF) in nutritionally 'high risk' patients receiving multimodal therapy for esophageal cancer. Patients were selected to undergo early JTF during neoadjuvant chemoradiotherapy (nCRT) in accordance with European Society for Clinical Nutrition and Metabolism (ESPEN) and Enhanced Recovery after Surgery (ERAS®) Society guidelines. Clinical outcomes were compared with patients who received routine JTF from the time of esophagectomy. Body composition was determined from computed tomography (CT) images acquired at diagnosis, after nCRT, and ≥3months after surgery. In total, 81 patients received early JTF and 91 patients received routine JTF. Patients who received early JTF had lower body mass index (BMI; 26.1±4.6 vs. 28.4±4.9; p=0.002), greater weight loss, and worse performance status at diagnosis. Groups were otherwise well-matched for baseline characteristics. Rate of re-intubation (8.8% vs. 1.1%; p=0.027), pulmonary embolism (5.0% vs. 0.0%; p=0.046), and 90-day mortality (10.0% vs. 1.1%; p=0.010) were worse in the early JTF group; however, overall survival was equivalent for both the early and routine JTF groups (p=0.053). Wide variation in the degree of preoperative muscle loss and total adipose tissue loss was observed across the entire study cohort. Relative preoperative muscle and adipose tissue loss in patients with early and routine JTF was equivalent. In patients determined to be at 'high risk' of malnutrition, early JTF may prevent excess morbidity after esophagectomy with an associated relative preservation of parameters of body composition.

Treatment Options for Lipodystrophy in Children.

Lipodystrophy includes a heterogeneous group of rare diseases characterized by different amounts of adipose tissue loss and several metabolic complications, including hypertriglyceridemia, steatohepatitis and particularly insulin resistance, that may lead to severe morbidity and, sometimes, mortality. Therefore, therapy for lipodystrophy primarily consists of a conventional approach that involves standard treatments of metabolic abnormalities. Given the evidence of leptin deficiency in lipodystrophy syndromes, leptin replacement therapy has been considered as a treatment option. Long-term studies on the use of therapy with a methionylated analog of human leptin, metreleptin, first on animals and subsequently on human patients, demonstrated enormous improvements of patients’ clinical features and metabolic conditions. Recently, metreleptin was approved by Food and Drug Administration (FDA) for the treatment of generalized lipodystrophy and by European Medicines Agency (EMA) for the treatment of both generalized and partial lipodystrophy. However, further research is being conducted for new and different therapeutic agents, especially helpful for the treatment of patients with partial lipodystrophy, as some of them do not have access to metreleptin therapy or show poor response.

Molecular Mechanisms and Current Treatment Options for Cancer Cachexia

Simple SummaryThe primary characteristics of cancer cachexia are weakness, weight loss, atrophy, fat reduction, and systemic inflammation. Cachexia is strongly associated with cancers involving the lungs, pancreas, esophagus, stomach, and liver, which account for half of all cancer deaths. TGF-β, MSTN, activin, IGF-1/PI3K/AKT, and JAK-STAT signaling pathways are known to underlie muscle atrophy and cachexia. Anamorelin (appetite stimulation), megestrol acetate, eicosapentaenoic acid, phytocannabinoids, targeting MSTN/activin, and molecules targeting proinflammatory cytokines, such as TNF-α and IL-6, are being tested as treatment options for cancer cachexia.Cancer cachexia is a condition marked by functional, metabolic, and immunological dysfunctions associated with skeletal muscle (SM) atrophy, adipose tissue loss, fat reduction, systemic inflammation, and anorexia. Generally, the condition is caused by a variety of mediators produced by cancer cells and cells in tumor microenvironments. Myostatin and activin signaling, IGF-1/PI3K/AKT signaling, and JAK-STAT signaling are known to play roles in cachexia, and thus, these pathways are considered potential therapeutic targets. This review discusses the current state of knowledge of the molecular mechanisms underlying cachexia and the available therapeutic options and was undertaken to increase understanding of the various factors/pathways/mediators involved and to identify potential treatment options.

The life of a Patient without Adipose Tissue: From Adipocyte Dysfunction to Metabolic Complications

Life without adipose tissue: Congenital generalized lipodystrophy; Origin, pathophysiology and therapeutic management Congenital Generalized Lipodystrophies also known as Berardinelli-Seip Congenital Lipodystrophy (BSCL) represent the most extreme phenotype of lipodystrophies. BSCLs are characterized by an almost total loss of adipose tissue and a predisposition to develop metabolic complications such as diabetes, hypertriglyceridemia ( hyperTG) and non-alcoholic fatty liver disease (NAFLD). Four subtypes of BSCL are distinguished according to the gene involved: AGPAT2 encoding the enzyme 1-acylglycerol-3-phosphate O acyltransferase 2, BSCL2 encoding Seipin, and more rarely CAV1 and PTRF encoding caveolae-associated proteins, respectively Caveolin-1, and Polymerase 1 and Transcription Releasing Factor (also known as Cavin-1). The study of the pathophysiology of BSCL, through clinical work and the generation of relevant animal and cellular models, has made it possible to understand how the absence of these proteins leads to primary and severe adipocyte dysfunction. It also highlights the critical importance of the adipose tissue in carbohydrate-lipid homeostasis, through its role as a storage site for energy molecules and its endocrine action. In this article, we will focus on the clinical features, molecular mechanisms, and treatment of congenital lipodystrophies. BSCL is an extreme phenotype that provides a unique opportunity to study the pathophysiological consequences of life without adipose tissue.

Impact of losing adipose tissue on outcomes from PD-1/PD-L1 inhibitor monotherapy in non-small cell lung cancer.

BackgroundAdipose tissue induces inflammation, which desensitizes the efficacy of immunotherapy. However, several reports show that the therapeutic effect of programed cell death 1 (PD‐1)/programed death‐ligand 1 (PD‐L1) inhibitor(s) monotherapy is significantly better in obese patients. Therefore, the effect of adipose tissue on immunotherapy is unclear.MethodsIn this study, we retrospectively reviewed patients with advanced non‐small cell lung cancer (NSCLC) who received PD‐1/PD‐L1 inhibitor monotherapy between May 2016 and December 2018. We classified patients into total adipose tissue maintenance or loss groups according to adipose tissue change during the 6 months before treatment and compared the therapeutic effect of PD‐1/PD‐L1 inhibitors between these groups along with the presence or absence of cachexia, a poor prognostic factor.ResultsOf the 74 patients, 40 (54.1%) were cachexic. Among cachexic patients, we found no clear difference in the overall response rate (ORR) and progression‐free survival (PFS) between the total adipose tissue maintenance and loss group. However, among noncachexic patients, the total adipose tissue loss group had a higher ORR (64.7% vs. 23.5%, p < 0.05) and longer PFS (18.5 months vs. 2.86 months, p = 0.037) than the maintenance group.ConclusionsThis study showed that decreasing adipose tissue without cachexia might favor the therapeutic effects of immunotherapy.

Brown adipose tissue involution associated with progressive restriction in progenitor competence.

Human brown adipose tissue (BAT) undergoes progressive involution. This involution process is not recapitulated in rodents, and the underlying mechanisms are poorly understood. Here we show that the interscapular BAT (iBAT) of rabbits whitens rapidly during early adulthood. The transcriptomic remodeling and identity switch of mature adipocytes are accompanied by loss of brown adipogenic competence of progenitors. Single-cell RNA sequencing reveals that rabbit and human iBAT progenitors highly express the FSTL1 gene. When iBAT involutes in rabbits, adipocyte progenitors reduce FSTL1 expression and are refractory to brown adipogenic recruitment. Conversely, FSTL1 is constitutively expressed in mouse iBAT to sustain WNT signaling and prevent involution. Progenitor incompetence and iBAT paucity can be induced in mice by genetic deletion of the Fstl1 gene or ablation of Fstl1+ progenitors. Our results highlight the hierarchy and dynamics of the BAT progenitor compartment and implicate the functional incompetence of FSTL1-expressing progenitors in BAT involution.

Adipocyte-specific CDK7 ablation leads to progressive loss of adipose tissue and metabolic dysfunction.

Adipose tissue regulates whole-body energy homeostasis. Both lipodystrophy and obesity, the extreme and opposite aspects of adipose tissue dysfunction, result in metabolic disorders: insulin resistance and hepatic steatosis. Cyclin-dependent kinases (CDKs) have been reported to be involved in adipose tissue development and functions. Using adipose tissue-specific knockout mice, here we demonstrate that the deletion of CDK7 in adipose tissue results in progressive lipodystrophy, insulin resistance, impaired adipokine secretion and downregulation of fat-specific genes, which are aggravated on high-fat diet and during ageing. Our studies suggest that CDK7 is a key regulatory component of adipose tissue maintenance and systemic energy homeostasis.

Loss of thymidine phosphorylase activity disrupts adipocyte differentiation and induces insulin-resistant lipoatrophic diabetes

BackgroundThymidine phosphorylase (TP), encoded by the TYMP gene, is a cytosolic enzyme essential for the nucleotide salvage pathway. TP catalyzes the phosphorylation of the deoxyribonucleosides, thymidine and 2′-deoxyuridine, to thymine and uracil. Biallelic TYMP variants are responsible for Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE), an autosomal recessive disorder characterized in most patients by gastrointestinal and neurological symptoms, ultimately leading to death. Studies on the impact of TYMP variants in cellular systems with relevance to the organs affected in MNGIE are still scarce and the role of TP in adipose tissue remains unexplored.MethodsDeep phenotyping was performed in three patients from two families carrying homozygous TYMP variants and presenting with lipoatrophic diabetes. The impact of the loss of TP expression was evaluated using a CRISPR-Cas9-mediated TP knockout (KO) strategy in human adipose stem cells (ASC), which can be differentiated into adipocytes in vitro. Protein expression profiles and cellular characteristics were investigated in this KO model.ResultsAll patients had TYMP loss-of-function variants and first presented with generalized loss of adipose tissue and insulin-resistant diabetes. CRISPR-Cas9-mediated TP KO in ASC abolished adipocyte differentiation and decreased insulin response, consistent with the patients’ phenotype. This KO also induced major oxidative stress, altered mitochondrial functions, and promoted cellular senescence. This translational study identifies a new role of TP by demonstrating its key regulatory functions in adipose tissue.ConclusionsThe implication of TP variants in atypical forms of monogenic diabetes shows that genetic diagnosis of lipodystrophic syndromes should include TYMP analysis. The fact that TP is crucial for adipocyte differentiation and function through the control of mitochondrial homeostasis highlights the importance of mitochondria in adipose tissue biology.

Non-linear Associations Between Visceral Adipose Tissue Distribution and Anthropometry-Based Estimates of Visceral Adiposity.

BackgroundRecent evidence suggests that excess visceral adipose tissue (VAT) is associated with future loss of subcutaneous adipose tissue (SAT) and skeletal muscle (SM) with aging. In clinical settings (abdominal) circumferences are commonly used to estimate body composition (BC). We aimed to study the linearity of VAT distribution ratios (i.e., VAT/SAT ratio and VAT/SM ratio), waist-to-hip ratio (WHR) and waist circumference (WC) with age and the relationship of VAT distribution ratios with anthropometry (i.e., WHR and WC).Materials and MethodsBC was determined using whole body magnetic resonance imaging in a large multi-ethnic group of 419 adults (42% white, 30% black, 15% Hispanic, 13% Asian, 1% other) with a BMI ranging from 15.9 to 40.8kg/m2. Linear and non-linear regression analysis was used to examine the linearity of VAT distribution ratios and anthropometry from 18 to 88 years. The relation between VAT distribution ratios and anthropometry was assessed separately.ResultsIn both sexes non-linear relationships were found between BC estimates and age, and between BC measures mutually. The ratios of VAT/SAT and VAT/SM showed quadratic relationships with age. VAT distribution ratios showed exponential or quadratic relationships with anthropometry with coefficients of determination ranging between 18 and 55%.ConclusionIn both sexes, VAT distribution ratios showed curvilinear relationships with age and with anthropometry. Given the sex differences in VAT distribution ratios, WHR and WC represent different BC proportions in men and women. These results emphasize the challenge when interpreting changes in BC based upon linear extrapolations in clinical practice.

Long-term and daily use of molecular hydrogen induces reprogramming of liver metabolism in rats by modulating NADP/NADPH redox pathways

Molecular hydrogen (H2) has emerged as a new therapeutic option in several diseases and is widely adopted by healthy people. However, molecular data to support therapeutic functions attributed to the biological activities of H2 remain elusive. Here, using transcriptomic and metabolomic approaches coupled with biochemistry and micro-CT technics, we evaluated the effect of long-term (6 months) and daily use of H2 on liver function. Rats exposed 2 h daily to H2 either by drinking HRW (H2 dissolved in H2O) or by breathing 4% H2 gas showed reduced lipogenesis and enhanced lipolysis in the liver, which was associated with apparent loss of visceral fat and brown adipose tissue together with a reduced level of serum lipids. Both transcripts and metabolites enriched in H2-treated rats revealed alteration of amino acid metabolism pathways and activation of purine nucleotides and carbohydrate biosynthesis pathways. Analysis of the interaction network of genes and metabolites and correlation tests revealed that NADP is the central regulator of H2 induced metabolic alterations in the liver, which was further confirmed by an increase in the level of components of metabolic pathways that require NADP as substrate. Evidence of immune response regulation activity was also observed in response to exposure to H2. This work is the first to provide metabolomic and transcriptomic data to uncover molecular targets for the effect of prolonged molecular hydrogen treatment on liver metabolism.

The burning furnace: Alteration in lipid metabolism in cancer-associated cachexia.

Cancer cachexia can be defined as a complex metabolic syndrome characterized by weight loss, anorexia, and emaciation due to the wasting of adipose tissue and skeletal muscle. In the last decade, much research has been done to decipher the role of lipid metabolism in cancer cachexia. Tumors, as well as host-derived factors, cause major metabolic changes in the body. Metabolic changes lead to higher energy expenditure by the host. To meet the high energy demand, the host utilizes fat depots stored in adipose tissues by a process known as lipolysis. High catabolic and low anabolic response leads to loss of adipose tissue. A significant insight has been made regarding adipose tissue "browning" bestow on thermogenic activities of adipocytes that result in catabolic energy expenditure. Both lipolysis and WAT browning play an important role in exhaustion adipose tissue. The goal of this review is to summarise what is currently known and about altered lipid metabolism and its utilization in cancer cachexia.

Liver disease and lipodystrophy: data from an Italian cohort

Background: Lipodystrophy syndromes (LS) are a group of rare disorders characterized by selective deficiency of adipose tissue, metabolic syndrome and eventually non-alcoholic fatty liver disease (NAFLD). Four major groups are described based on etiology (genetic/ acquired) and distribution of adipose tissue loss (generalized/partial). Aim of the study was to describe liver profiles in a cohort of patients with congenital and acquired LS.