Reduced Adipose Tissue Research Articles

Efficacy and Safety of TANIT Platform Combining Dampened Bioactive Current and Functional Dermal Stimulation for the Treatment of Adipose Tissue in Patients with Stage I or II Lipedema.

Purpose: The study's main objective was to assess the efficacy and safety of TANIT, a platform combining functional dermal stimulation with damped bioactive current and mechanical stimulation to reduce adipose tissue (AT) in patients with stage I (SI) or II (SII) lipedema. Methods: A single-center, before-after clinical trial without a control group was conducted on adult women diagnosed with SI or SII lipedema. Patients underwent a treatment protocol for 5 weeks, with weekly sessions. Blood tests, AT thickness, pain threshold, and anthropometric measurements were assessed at baseline and the end of the study, and a satisfaction survey was conducted after treatment. Results: Twenty-three women were enrolled with a mean age of 44.91 (standard deviation 11.58) and a median of 46.00 (Q25 = 36.50, Q75 = 51.50). Seven (30.4%) patients had SI lipedema and 16 (69.6%) had SII. The pain threshold increased in 78.3% of patients at the knee level and 80.0% at the ankle level. Lower limb volume decreased in 78.3% of patients. AT thickness decreased in all treated areas, with a mean decrease of 26.1% at the ankles, 14.5% at the knees, and 17.4% at the trochanter level. Patients reported high satisfaction with the results obtained after the treatment sessions, and no unexpected adverse effects were found. Conclusions: The TANIT platform provided an effective and safe conservative treatment option for patients with S and SII lipedema, reducing leg volume, AT thickness, and pain. However, additional randomized clinical trials and standardized assessment tools would be necessary.

Effects of liraglutide on body composition in people living with obesity or overweight: A systematic review.

To evaluate the effect of liraglutide on body composition in people living with obesity or overweight. A systematic search was conducted in PubMed, Embase, and Cochrane Library databases up to June 10, 2024. Randomized controlled trials (RCTs) comparing liraglutide to placebo and reporting body composition outcomes were included. Data from 15 studies involving 960 participants were analyzed. Liraglutide consistently demonstrated significant reductions in total weight, fat mass, and visceral adipose tissue (VAT) compared to placebo across the included studies. VAT reductions ranged from 12.49 % to 23 %, highlighting liraglutide's effectiveness in targeting visceral fat, a key factor in cardiometabolic risk. Fat mass reductions were also substantial and consistent, reinforcing the efficacy of liraglutide in improving overall body composition. In contrast, lean mass outcomes were more variable, with some studies reporting preservation or even gains in lean mass, while others indicated losses. Liraglutide effectively reduces fat mass and VAT, supporting its use in managing obesity and related cardiometabolic risks. However, the inability to accurately calculate lean and fat mass proportions underscores the need for standardized reporting and availability of individual-level data. Future research should prioritize these elements and include muscle function assessments to better evaluate the clinical impacts of GLP-1 receptor agonists on body composition.

GDF15-GFRAL signaling drives weight loss and lipid metabolism in mouse model of amyotrophic lateral sclerosis.

Weight loss is a common early sign in amyotrophic lateral sclerosis (ALS) patients and negatively correlates with survival. In different cancers and metabolic disorders, high levels of serum growth differentiation factor 15 (GDF15) contribute to a decrease of food intake and body weight, acting through GDNF family receptor alpha-like (GFRAL). Here we report that GDF15 is highly expressed in the peripheral blood of ALS patients and in the hSOD1G93A mouse model and that GFRAL is upregulated in the brainstem of hSOD1G93A mice. We demonstrate that the localized GFRAL silencing by shRNA in the area postrema/nucleus tractus solitarius of hSOD1G93A mice induces weight gain, reduces adipose tissue wasting, ameliorates the motor function and muscle atrophy and prolongs the survival time. We report that microglial cells could be involved in mediating these effects because their depletion with PLX5622 reduces brainstem GDF15 expression, weight loss and the expression of lipolytic genes in adipose tissue. Altogether these results reveal a key role of GDF15-GFRAL signaling in regulating weight loss and the alteration of and lipid metabolism in the early phases of ALS.

P0751 The effects of high and low emulsifier diets in active Crohn’s disease: A pilot double-blinded randomised feeding trial

Abstract Background Preclinical studies implicate dietary emulsifiers as detrimental to patients with Crohn’s disease. We aimed to examine the effect of high- and low-emulsifiers diets on intestinal inflammation in adults with ileal Crohn’s disease. Methods In a pilot double-blinded, randomized, controlled feeding study, patients with symptomatic and sonographically active Crohn’s disease with ileal involvement on stable medical therapy were randomized to received four weeks of an isocaloric high (HED) or low (LED) emulsifier diet modelled on Australian healthy eating guidelines. Evaluation of objective markers (faecal calprotectin, C-reactive protein, sonographic indices), clinical disease activity (Harvey Bradshaw Index), body composition (waist circumference, visceral adipose tissue via bioimpedance and quantitative muscle ultrasound) and quality of life were measured at baseline and at study completion. Results Of 116 patients screened, 24, mean age 37 (95% CI 32, 41) years, 12 male, were randomized. Five participants (2 HED, 3 LED) withdrew due to increased gastrointestinal symptoms. Dietary adherence was excellent. On ultrasound, IBUS-SAS fell from 51 (35, 68) to 33 (15, 51) on HED (p=0.014) and from 57 (38, 76) to 44 (29, 59) on LED (p=0.010) with no difference between diets (p=0.28). C-reactive protein and faecal calprotectin did not change overall. 9/12 on HED and 7/12 on LED entered clinical remission (Harvey Bradshaw Index ≤4). Quality of life improved on both diets (both p<0.003) as did fatigue (both p≤0.050). The HED and LED reduced weight by 2.2 [1.3,3.2] kg (p=0.009), waist circumference by 4% (p<0.001) and visceral adipose tissue by 16% (p<0.001) without a change of quantitative muscle ultrasound (p=0.78).There was no difference in any outcomes between the diets. Conclusion Emulsifiers in the food supply have no effect on intestinal inflammation in patients with active ileal Crohn’s disease, but a diet that follows healthy eating principles was associated with reduction of intestinal inflammation, clinical remission, improved quality of life and fatigue scores with reduction of visceral adipose tissue whilst maintaining lean muscle mass. Australian New Zealand Clinical Trials Registry (ACTRN12619000980134).

Timing of exercise differentially impacts adipose tissue gain in male adolescent rats.

Circadian rhythms of metabolic, hormonal, and behavioral fluctuations and their alterations can impact health. An important gap in knowledge in the field is whether the time of the day of exercise and the age of onset of exercise exert distinct effects at the level of whole-body adipose tissue and body composition. The goal of the present study was to determine how exercise at different times of the day during adolescence impacts the adipose tissue transcriptome and content in a rodent model. Rats were subjected to one of four conditions during their adolescence: early active phase control or exercise (EAC or EAE; ZT13), and late active phase control or exercise (LAC or LAE; ZT23). The effects of exercise timing were assessed at the level of subcutaneous and visceral adipose tissue transcriptome, body composition, hypothalamic expression of orexigenic and anorexigenic genes, blood serum markers and 24-hour core body temperature patterns. We found that late active phase exercise (ZT23) greatly upregulated pathways of lipid synthesis, glycolysis and NADH shuttles in LAE rats, compared to LAC or EAE. Conversely, LAE rats showed notably lower content of adipose tissue. In addition, LAE rats showed signs of impaired FGF21-adiponectin axis compared to other groups. Finally, LAE rats showed higher post-exercise core body temperature compared to other groups. Our results thus indicate that our exercise protocol induced an unusual effect characterized by enhanced lipid synthesis but reduced adipose tissue content in late active phase but not early active phase exercise during adolescence.

Associations between systemic immune-inflammatory index and visceral adipose tissue area: results of a national survey.

Global health issues related to obesity are growing. Visceral adipose tissue (VAT) significantly contributes to complications associated with obesity. Reducing adipose tissue accumulation can improves inflammation. However, it is still unknown how the systemic immune-inflammation index (SII) and VAT area are related. With the help of multivariate linear regression and smooth curve fitting, the relationship between SII and VAT area was explored with data from the 2013 and 2014 National Health and Nutrition Examination Survey (NHANES). Analyzing subgroups and testing for interaction were used to investigate whether the relationship was accurate across demographics. From 20 to 59 years of age, 3,290 individuals were observed to have a positive correlation between SII and VAT area. In accordance with the fully adjusted model, the VAT area increased by 9.34 cm2 for every unit increase in log SII [β = 9.34, 95% CI (4.02, 14.67)]. In the highest quartile of SII, the VAT area was 5.46 cm2 [β = 5.46, 95% CI (2.21, 8.71)] higher than that in the lowest quartile. Additionally, the population that was overweight or obese showed a stronger positive correlation. SII has a positive correlation with VAT area in US adults. SII may be valuable in clinical applications to evaluate the severity of VAT area.

Astrocyte Loss Augments Body Weight Through Reduction in Adipose Sympathetic Outflows.

Emerging evidence indicates that astrocytes modulate energy metabolism and homeostasis. However, one important but poorly understood element is the necessity of astrocytes in the control of body weight. Here, we apply viral vector-assisted brain-region selective loss of astrocytes to define physiological roles played by astrocytes in the arcuate nucleus of the hypothalamus (ARH) and to elucidate the involved mechanism. We find that astrocyte loss potently augments body weight in adult mice fed chow or high-fat diet. Mechanistically, we find that the loss of astrocytes reduces adipose tissue norepinephrine (NE) contents and chemogenetic stimulation of adipose tissue sympathetic inputs reverses the astrocyte loss-induced increase in body weight. Collectively, our findings in this study suggest a crucial physiological role of astrocytes in preventing diet-induced energy surfeit and obesity by modulating adipose tissue lipid metabolism through central sympathetic outflows to adipose tissues.

GDF15 inhibits early-stage adipocyte differentiation by enhancing HOP2 expression and suppressing C/EBPα expression.

Excessive adipocyte differentiation and accumulation contribute to the development of metabolic disorders. Growth differentiation factor 15 (GDF15) plays an essential role in energy homeostasis and is considered an anti-obesity factor; however, elevated serum levels of endogenous GDF15 have been reported in certain individuals with obesity. In this study, to gain a better understanding of this complex relationship between GDF15 levels and obesity, we investigated GDF15 expression and function during adipogenesis. Compared with mice fed a normal diet, those fed a short-term high-fat diet exhibited a reduction in epididymal white adipose tissue and serum GDF15 expression. These results were confirmed in human adipose-derived stem cells that showed reduced GDF15 expression during adipogenesis differentiation. During adipogenesis, GDF15 was primarily degraded via the autophagy lysosomal pathway, and GDF15 overexpression in pre-adipocytes inhibited adipogenesis by suppressing CCAAT enhancer binding protein alpha (C/EBPα). Furthermore, whereas we detected a reduction in homologous-pairing protein 2 (HOP2) expression during adipogenesis, expression increased in response to an overexpression of GDF15. Furthermore, following knockdown of HOP2 during GDF15 overexpression, there was no suppression of C/EBPα expression. These findings indicate that GDF15 undergoes lysosomal degradation via an autophagic pathway and suppresses adipocyte differentiation via the HOP2-mediated inhibition of C/EBPα expression. Collectively, our findings indicate that GDF15 could serve as a potential therapeutic target for the treatment of metabolic disorders.

Rspo3-mediated metabolic liver zonation regulates systemic glucose metabolism and body mass in mice.

The unique architecture of the liver consists of hepatic lobules, dividing the hepatic features of metabolism into 2 distinct zones, namely the pericentral and periportal zones, the spatial characteristics of which are broadly defined as metabolic zonation. R-spondin3 (Rspo3), a bioactive protein promoting the Wnt signaling pathway, regulates metabolic features especially around hepatic central veins. However, the functional impact of hepatic metabolic zonation, regulated by the Rspo3/Wnt signaling pathway, on whole-body metabolism homeostasis remains poorly understood. In this study, we analyze the local functions of Rspo3 in the liver and the remote actions of hepatic Rspo3 on other organs of the body by using murine models. Rspo3 expression analysis shows that Rspo3 expression patterns are spatiotemporally controlled in the murine liver such that it locates in the pericentral zones and converges after feeding, and the dynamics of these processes are disturbed in obesity. We find that viral-mediated induction of Rspo3 in hepatic tissue of obesity improves insulin resistance and prevents body weight gain by restoring attenuated organ insulin sensitivities, reducing adipose tissue enlargement and reversing overstimulated adaptive thermogenesis. Denervation of the hepatic vagus suppresses these remote effects, derived from hepatic Rspo3 induction, toward adipose tissues and skeletal muscle, suggesting that signals are transduced via the neuronal communication consisting of afferent vagal and efferent sympathetic nerves. Furthermore, the non-neuronal inter-organ communication up-regulating muscle lipid utilization is partially responsible for the ameliorations of both fatty liver development and reduced skeletal muscle quality in obesity. In contrast, hepatic Rspo3 suppression through Cre-LoxP-mediated recombination system exacerbates diabetes due to glucose intolerance and insulin resistance, promotes fatty liver development and decreases skeletal muscle quality, resulting in obesity. Taken together, our study results reveal that modulation of hepatic Rspo3 contributes to maintaining systemic glucose metabolism and body composition via a newly identified inter-organ communication mechanism.

Heat acclimation defense against exertional heat stroke by improving the function of preoptic TRPV1 neurons.

Rationale: Record-breaking heatwaves caused by greenhouse effects lead to multiple hyperthermia disorders, the most serious of which is exertional heat stroke (EHS) with the mortality reaching 60 %. Repeat exercise with heat exposure, termed heat acclimation (HA), protects against EHS by fine-tuning feedback control of body temperature (Tb), the mechanism of which is opaque. This study aimed to explore the molecular and neural circuit mechanisms of the HA training against EHS. Methods: Male C57BL/6 mice (6-8 weeks) and male TRPV1-Cre mice (6-8 weeks) were used in our experiments. The EHS model with or without HA training were established for this study. RNA sequencing, qPCR, immunoblot, immunofluorescent assays, calcium imaging, optogenetic/ chemical genetic intervention, virus tracing, patch clamp, and other methods were employed to investigate the molecular mechanism and neural circuit by which HA training improves the function of the medial preoptic area (mPOA) neurons. Furthermore, a novel exosome-based strategy targeting the central nervous system to deliver irisin, a protective peptide generated by HA, was established to protect against EHS. Results: HA-related neurons in the mPOA expressing transient receptor potential vanilloid-1 (TRPV1) were identified as a population whose activation reduces Tb; inversely, dysfunction of these neurons contributes to hyperthermia and EHS. mPOATRPV1 neurons facilitate vasodilation and reduce adipose tissue thermogenesis, which is associated with their inhibitory projection to the raphe pallidus nucleus (RPa) and dorsal medial hypothalamus (DMH) neurons, respectively. Furthermore, HA improves the function of preoptic heat-sensitive neurons by enhancing TRPV1 expression, and Trpv1 ablation reverses the HA-induced heat tolerance. A central nervous system-targeted exosome strategy to deliver irisin, a protective peptide generated by HA, can promote preoptic TRPV1 expression and exert similar protective effects against EHS. Conclusions: Preoptic TRPV1 neurons could be enhanced by HA, actively contributing to heat defense through the mPOA"DMH/RPa circuit during EHS, which results in the suppression of adipose tissue thermogenesis and facilitation of vasodilatation. A delivery strategy of exosomes engineered with RVG-Lamp2b-Irisin significantly improves the function of mPOATRPV1 neurons, providing a promising preventive strategy for EHS in the future.

Pediococcus acidilactici Y01 reduces HFD-induced obesity via altering gut microbiota and metabolomic profiles and modulating adipose tissue macrophage M1/M2 polarization.

Obesity-related metabolic syndrome is intimately associated with infiltrated adipose tissue macrophages (ATMs), gut microbiota, and metabolic disorders. Pediococcus acidilactici holds the potential to mitigate obesity; however, there exist strain-specific functionalities and diverse mechanisms, which deserve extensive exploration. This study aims to explore the potential of P. acidilactici Y01, isolated from traditional sour whey, in alleviating HFD-induced metabolic syndrome in mice and elucidating its underlying mechanism. The results showed that P. acidilactici Y01 could inhibit the increase of body weight gain, the deposition of fat, lipid disorders and chronic low-grade inflammation, improve glucose tolerance and insulin resistance, and could reduce adipose tissue inflammation by decreasing M1-type ATMs and increasing M2-type ATMs. Meanwhile, P. acidilactici Y01 significantly increased the abundance of potentially beneficial intestinal bacteria, such as Akkermansia, Alistipes, Bifidobacterium, Lachnospiraceae_NK4A136_group, Lactobacillus, norank_f__Muribaculaceae, and Parabacteroides, and partially restored the levels of metabolites, such as phosphatidylcholines, glycerophosphocholines, sphingolipids and unsaturated fatty acids. The fecal microbiota transplantation experiment demonstrated that P. acidilactici Y01 ameliorated obesity-related metabolic syndrome by modulating the polarization of M1/M2 ATMs mediated by gut microbiota. Overall, as a dietary supplement, P. acidilactici Y01 has good potential in the prevention and treatment of obesity.

Linsitinib inhibits IGF-1-induced cell proliferation and hyaluronic acid secretion by suppressing PI3K/Akt and ERK pathway in orbital fibroblasts from patients with thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO), an autoimmune disorder of the retrobulbar tissue, is present in up to 50 percent of Graves's hyperthyroidism patients. Insulin-like growth factor 1 receptor (IGF-1R) has received attention as a target for the development of therapeutic agent for TAO. IGF-1R and TSHR (thyroid stimulating hormone receptor) interact with each other to form a physical or functional complex, further promoting the development of TAO. Linsitinib, OSI-906, is an inhibitor of IGF-1R and has been reported to inhibit cell proliferation of several tumor cells. Linsitinib has been receiving attention not only for its anticancer effect, but also for its anti-inflammatory effects. It has been reported that linsitinib reduces infiltration of inflammatory cells in orbital tissues, resulting in the reduction of muscle edema and adipose tissues in an experimental murine model for Graves' disease. In the current study, we investigated the issue of whether linsitinib inhibits the IGF-1-induced proliferation of orbital fibroblasts (OFs) via the suppression of phosphatidylinositol 3-kinase (PI3K) / Akt and extracellular signal-regulated kinase (ERK) pathway. Our results showed that pretreatment with linsitinib inhibited IGF-1-induced cell proliferation and hyaluronic acid secretion in the OFs of TAO patients. In addition, our results showed that pretreatment with linsitinib inhibited IGF-1-induced phosphorylation of IGF-1Rβ at Tyr1135, Akt at Ser473, and ERK in the OFs of patients with TAO. These results indicate that linsitinib inhibits IGF-1-induced cell proliferation and hyaluronic acid secretion in the OFs of TAO patients by suppressing the PI3K/Akt and ERK pathways, validating the use of linsitinib as a novel therapeutic agent for TAO.

In Vitro Evaluation of Probiotic Activities and Anti-Obesity Effects of Enterococcus faecalis EF-1 in Mice Fed a High-Fat Diet.

This research sought to assess the anti-obesity potential of Enterococcus faecalis EF-1. An extensive and robust in vitro methodology confirmed EF-1's significant potential in combating obesity, probably due to its excellent gastrointestinal tract adaptability, cholesterol-lowering property, bile salt hydrolase activity, α-glucosidase inhibition, and fatty acid absorption ability. Moreover, EF-1 exhibited antimicrobial activity against several pathogenic strains, lacked hemolytic activity, and was sensitive to all antibiotics tested. To further investigate EF-1's anti-obesity properties in vivo, a high-fat diet (HFD) was used to induce obesity in C57BL/6J mice. Treatment with EF-1 (2 × 109 CFU/day) mitigated HFD-induced body weight gain, reduced adipose tissue weight, and preserved liver function. EF-1 also ameliorated obesity-associated microbiota imbalances, such as decreasing the Firmicutes/Bacteroidetes ratio and boosting the levels of bacteria (Faecalibacterium, Mucispirillum, Desulfovibrio, Bacteroides, and Lachnospiraceae_NK4A136_group), which are responsible for the generation of short-chain fatty acids (SCFAs). Concurrently, the levels of total SCFAs were elevated. Thus, following comprehensive safety and efficacy assessments in vitro and in vivo, our results demonstrate that E. faecalis EF-1 inhibits HFD-induced obesity through the regulation of gut microbiota and enhancing SCFA production. This strain appears to be a highly promising candidate for anti-obesity therapeutics or functional foods.

Brown Rice: A Promising Therapeutic Strategy for Reducing Inflammatory Markers in the Adipose Tissue of Diet-Induced Obesity Rat Model

Obesity is closely linked to adipose tissue inflammation, where macrophages play a crucial role. One approach to enhance the issue of obesity is by implementing nutritional intervention. This study designed to investigate the impact of administering brown rice and gamma oryzanol (ORZ) on reducing adipose tissue expansion and inflammation in a rat model of diet-induced obesity. The study involved male Sprague-Dawley rats of the Rattus novergicus strain. The negative control group received AIN93M as the standard diet, while the remaining were induced to become obese by high-fat, high fructose (HFHFr) diet. Then, we divided them into 4 treatment groups: mix HFHFr diet with brown rice; white rice; white rice + ORZ; and ORZ only. Treatment was given for 12 weeks. Histological examination was used to measure both the size and number of adipocytes. Immunohistochemical staining was done to evaluate the infiltration of macrophages into adipose tissue, while immunofluorescence labelling was utilized to examine the expression of macrophages M1 and M2. The addition of brown rice and ORZ appears to improve adipocyte expansion. The brown rice group showed the least amount of M1 macrophages, while the negative control group showed the highest amount of M2 macrophages, leading to much lower M1/M2 ratios compared to the other groups. No differences were found in the study of variables in either visceral or subcutaneous adipose tissue. Brown rice and ORZ can potentially improve adipose tissue expansion and suppress the expression of pro-inflammatory macrophages.

Clinical Protocol Effects With LED Photobiomodulation for Reducing Adipose Tissue in the Abdomen Region.

Reverse the fat accumulation and to improve body contouring with more safely than invasive procedures has become a necessary therapeutic approach, but little detailed when using LED photobiomodulation. To evaluate an application protocol with two different wavelengths (red and infrared LED) consecutively in the abdomen region alone or associated with the dermocosmetics application with lipolytic properties. Ninety patients with a significant amount of adipose tissue in the abdomen region were selected and randomized into three groups: Sham (SG), in which patients received a simulation of the treatment; LED (LG), in which participants received the application with LED; LED with dermocosmetic (LDG), in which the participants underwent a combination of LED and dermocosmetic treatment. The following assessments were carried out: anthropometric data (weight, height, perimetry, and adipometry); ultrasound examination to adipose layer; patient satisfaction questionnaire; histology of a donated a tissue sample. The main findings were a decrease in umbilical perimetry, a significant decrease in the body fat layer determined by ultrasound and significant histological changes that indicated an improvement in the appearance of the skin and an increase in the amount of macrophages in the subcutaneous layer. Histological data also showed an improvement in the appearance of the skin with an increase in collagen deposition and an increase in macrophages in the subcutaneous layer. The LED phototherapy application protocol, both alone and in association with the dermocosmetic, with the emission of two consecutive wavelengths, was effective in reducing the fat tissue in the abdomen region.

Handgrip strength, cardiometabolic risk and body composition in youth with type 1 diabetes: the Diactive-1 Cohort Study

ObjectiveThis study aimed to explore the association between handgrip strength, cardiometabolic risk (CMR) and body composition in youth with type 1 diabetes.MethodsFor this prospective cohort study, muscular fitness was assessed...

Silymarin-Enriched Extract from Milk Thistle Activates Thermogenesis in a Preclinical Model of High-Fat-Diet-Induced Obesity to Relieve Systemic Meta-Inflammation.

Obesity and aging are associated with the progressive loss of brown adipose tissue (BAT), an increase in visceral white adipose tissue (vWAT), and a reduction in subcutaneous white adipose tissue (sWAT). The progressive expansion of visceral obesity promotes a low grade of systemic chronic inflammation (meta-inflammation), contributing to the onset of comorbidities such as type 2 diabetes mellitus (T2DM), metabolic syndrome, and even cancer. Thus, preserving the thermogenic activity of adipose tissue and improving the metabolic flexibility of sWAT could be an effective strategy to prevent the development of metabolic chronic diseases and promote healthy aging. Precision nutrition has emerged as a complementary approach to control the metabolic alterations associated with unhealthy obesity and aging. In a previous work, we described that a silymarin-enriched extract from milk thistle (Mthistle) increased markers of browning and thermogenesis in vitro in human differentiated adipocytes (SGBS). Therefore, this study aims to evaluate the potential of Mthistle to activate thermogenesis in a preclinical model of high-fat diet (HFD)-induced obesity (DIO). Our results demonstrate that Mthistle increases systemic energy expenditure (EE), preserves body temperature after cold exposure, improves insulin resistance, and reduces inflammatory markers in WAT. Based on these results, silymarin-enriched extract from Mthistle may be proposed as a nutraceutical for the management of metabolic chronic diseases and/or accelerated aging.

Health-related fitness benefits following concurrent high-intensity interval training and resistance training in patients with type-1 diabetes or type-2 diabetes.

Cardiorespiratory fitness (CRF), as assessed by VO2peak, along with metabolic and cardiovascular health indices, represents the strongest predictors of survival. However, it remains unclear whether concurrent high-intensity interval training (HIIT) and resistance training (RT) can similarly enhance these health markers in patients with type-1 diabetes (T1D) or type-2 diabetes (T2D) compared to healthy individuals. Adults with uncomplicated T1D or T2D and healthy normoglycemic controls matched for sex and age (HC1 and HC2) performed 3 training sessions/week of concurrent HIIT and RT for 12 weeks. Pre- and post-intervention assessments included: lipids and glycemic profile, body composition (dual-energy x-ray absorptiometry) and a cyclo-ergometric cardio-pulmonary exercise test. Training improved VO2peak, the ventilatory threshold (VT1), maximal workload, ventilation and O2pulse, similarly in T1D in HC1 without changes in body composition or glycemic profile. In patients with T2D, training improved insulin sensitivity (HOMA-IR), lean mass, VE/VCO2 slope, VT1 and maximal O2pulse, workload and VO2peak with reduction in fat mass and visceral adipose tissue (VAT) (all, p < 0.05). However, improvements in VO2peak and O2pulse were lower than in healthy controls (respectively, T2D: +9%, HC2: +18% and T2D: +6%, HC2: +19%, p < 0.05). Both patients with T1D and T2D benefit from combined HIIT and RT by improving CRF with specific adaptations influenced by the presence and type of diabetes. While identical magnitude of achievements were observed in T1D and HC1, T2D patients exhibited lower VO2peak and maximal O2pulse improvements but associated with notable additional health benefits regarding insulin sensitivity, body composition, visceral adipose tissue and ventilatory efficiency.

Abstract PR007: Pancreatic cancer cachexia is mediated by tumor-derived PTHrP

Abstract Purpose: Our prior work has established that metastasis is initiated by PTHrP-driven mechanisms in pancreatic ductal adenocarcinoma (PDAC). PTHLH (the gene encoding the PTHrP protein) is directly adjacent to and co-amplified along with KRAS, the major oncogenic driver in PDAC patients. The KRAS-PTHLH amplicon is a marker of the highly aggressive squamous/quasi-mesenchymal/basal-like PDAC patient subtypes, is associated with increases in metastasis and cancer cachexia, and correlates with decreased overall patient survival. We have deleted Pthlh in the autochthonous Kras- and Tp53-driven pancreatic cancer mouse model (i.e. KPC mice) and found that the resulting KPC-Pthlh LoxP mice (herein KPC-PthrpcKO) live nearly twice as long as KPC controls. Intriguingly, recent evidence has emerged for PTHrP’s role in cachexia-associated adipose tissue wasting and we posit that the dramatic survival extension in KPC-PthrpcKO mice may be due to reduced cachexia. Results: In PDAC patients, PTHrP is co-amplified along with KRAS and correlates with significantly decreased overall survival. We generated KPC-PthrpcKO mice and showed that they have reduced tumor burden and dramatically increased overall survival relative to KPC controls. In parallel experiments, we treated mice with an anti-PTHrP neutralizing monoclonal antibody, which similarly extended survival. Upon further analysis, we observed that the overall body condition of KPC-PthrpcKO mice (and anti- PTHrP treated KPC mice) was greatly improved, with less loss of adipose and muscle tissue. Mechanistic studies revealed that tumor cell-derived PTHrP signaling to adipocytes in white adipose tissue depots mediates cachexia. Specifically, we found that adipose tissue wasting and lipolysis were greatly reduced upon deletion or pharmacological inhibition of PTHrP. In the same vein, RNA-seq of cachectic adipose tissue revealed that PTHrP mediates adipose wasting by turning off de novo lipogenesis (DNL), a process critical for the generation of fatty acids in adipocytes. PTHrP binds to its cognate receptor, PTH1R, on adipocytes and blocks fatty acid synthesis by turning off the essential DNL transcription factors CHREBP and SREBP, likely through a PTH1R-PKA-CREB1 signaling axis. Thus, the genetic deletion and pharmacological inhibition of PTHrP in vivo led to a profound reduction in cachexia-related adipose tissue wasting and muscle atrophy. Re-introduction of PTHrP into a PDAC cell line with low cachexia-inducing potential (and low baseline PTHrP) dramatically increased the degree of cachexia observed upon orthotopic implantation, leading to a reduction in overall survival. Therefore, PTHrP is both necessary and sufficient to induce cachexia in pancreatic cancer. Conclusions: This work has demonstrated the importance of the previously unappreciated roles of PTHrP signaling in driving pancreatic cancer cachexia and adipose tissue remodeling, and future studies will look to translate anti-PTHrP therapy into clinical trials. Citation Format: Jason Pitarresi. Pancreatic cancer cachexia is mediated by tumor-derived PTHrP [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR007.

Rapid downregulation of DICER is a hallmark of adipose tissue upon high-fat diet feeding

Adipose tissue regulates whole-body energy balance and is crucial for metabolic health. With energy surplus, adipose tissue expands, which may lead to local areas of hypoxia and inflammation, and consequently impair whole-body insulin sensitivity. We report that DICER, a key enzyme for miRNA maturation, is significantly lower in abdominal subcutaneous white adipose tissue of men with obesity compared with men with a lean phenotype. Furthermore, DICER is profoundly downregulated in mouse adipose tissue and liver within the first week on a high-fat diet (HFD), and remains low after prolonged HFD feeding. Downregulation of DICER in mice occurs in both mature adipocytes and stromal vascular cells. Mechanistically, chemically induced hypoxia in vitro shows DICER degradation via interaction with hypoxia-inducible factor 1-α (HIF1α). Moreover, DICER and HIF1α interact in brown adipose tissue post-HFD which may signal for DICER degradation. Finally, RNA sequencing reveals a striking time-dependent downregulation of total miRNA content in mouse subcutaneous adipose tissue after HFD feeding. Collectively, HFD in mice reduces adipose tissue DICER, likely due to hypoxia-induced interaction with HIF1α during tissue expansion, and this significantly impacts miRNA content.