Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of oxytocin-elicited reductions of body weight and adiposity in male diet-induced obese mice.

Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (TIBAT, a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase TIBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9 ± 2.0, 77.4 ± 12.7 and 93.6 ± 4.6% (P<0.05), respectively and was unchanged in inguinal white adipose tissue, pancreas or liver. We subsequently measured the effects of acute 4V OT (1, 5 µg ≈ 0.99, 4.96 nmol) on TIBAT in DIO mice following sham or bilateral surgical SNS denervation to IBAT. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) elevated TIBAT similarly in sham mice as in denervated mice. We subsequently measured the effects of chronic 4V OT (16 nmol/day over 29 days) or vehicle infusions on body weight, adiposity and food intake in DIO mice following sham or bilateral surgical denervation of IBAT. Chronic 4V OT reduced body weight by 5.7 ± 2.23% and 6.6 ± 1.4% in sham and denervated mice (P<0.05), respectively, and this effect was similar between groups (P=NS). OT produced corresponding reductions in whole body fat mass (P<0.05). Together, these findings support the hypothesis that sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and reductions of body weight and adiposity in male DIO mice.

Long-term changes in adiposity markers during and after antidepressant therapy in a community cohort.

Research on antidepressant-related weight changes over more than 12 months is scarce and adjustment for the effects of depressive episodes has rarely been applied. Accordingly, our aim was to assess the associations of the use of any antidepressants, subclasses of antidepressant and specific compounds prior to baseline and during a 5.5-year follow-up with changes in adiposity markers, and the effect of sex on these associations, with adjustment for multiple confounders including the effects of depressive episodes and their severity. Data stemmed from a prospective cohort study including 2479 randomly selected 35-66 year-old residents of an urban area (mean age 49.9 years, 53.3% women) who underwent physical and psychiatric evaluations at baseline and follow-up. Weight, height, waist circumference, and body fat were measured by trained nurses and information on diagnosis and antidepressant use prior to baseline and during follow-up was collected through standardized interviews. In the fully adjusted models, the number of antidepressants, mainly SSRIs and TCAs, used prior to baseline, was associated with a lower increase of body-mass index (BMI, ß (95%CI) = -0.12 (-0.19, -0.05)) and waist circumference (ß = -0.28 (-0.56, -0.01)), whereas participants treated with antidepressants during the follow-up had a steeper increase in BMI (ß = 0.32 (0.13, 0.50)) and waist circumference (ß = 1.23 (0.44, 2.01)). Within the class of SSRIs, the use of fluoxetine, sertraline or escitalopram during follow-up was associated with a steeper increase in adiposity markers. The associations of SSRIs with BMI and waist circumference were only observed when the SSRIs were used during the second period of the follow-up. Sex did not moderate these associations. Our findings suggest an increase of adiposity markers during sustained treatment with TCAs and SSRIs, which however return to normal levels after cessation of treatment. Hence, the benefit of long-term administration of these antidepressants should be carefully weighed against the potential risk of weight gain.

GPR55 Antagonist CID16020046 Attenuates Obesity-Induced Airway Inflammation by Suppressing Chronic Low-Grade Inflammation in the Lungs.

GPR55 is a receptor for lysophosphatidylinositols (LPIs) in digestive metabolites. Overnutrition leads to obesity, insulin resistance, and increased LPI levels in the plasma. The involvement of LPIs and GPR55 in adiposity, hepatic steatosis, and atherosclerosis has been previously elucidated. However, the therapeutic efficacy of GPR55 antagonists against obesity-induced airway inflammation has not been studied. The present study investigated whether CID16020046, a selective antagonist of GPR55, could modulate obesity-induced airway inflammation caused by a high-fat diet (HFD) in C57BL/6 mice. Administration of CID16020046 (1 mg/kg) inhibits HFD-induced adiposity and glucose intolerance. Analysis of immune cells in BALF showed that CID16020046 inhibited HFD-induced increase in immune cell infiltration. Histological analysis revealed the HFD induced hypersecretion of mucus and extensive fibrosis in the lungs. CID16020046 inhibited these HFD-induced pathological features. qRT-PCR revealed the HFD-induced increase in the expression of Ifn-γ, Tnf-α, Il-6, Il-13, Il-17A, Il-1ß, Nlrp3, and Mpo mRNAs in the lungs. CID16020046 inhibited the HFD-induced increases in these genes. The expression levels of adipokines were regulated by the HFD and CID16020046. AdipoQ in the lungs and gonadal white adipose tissue was decreased by the HFD and reversed by CID16020046. In contrast, Lep was increased by the HFD and suppressed by CID16020046. The findings suggest the potential application of the GPR55 antagonist CID16020046 in obesity-induced airway inflammation.

Adiposity in mares induces insulin dysregulation and mitochondrial dysfunction which can be mitigated by nutritional intervention.

Obesity is a complex disease associated with augmented risk of metabolic disorder development and cellular dysfunction in various species. The goal of the present study was to investigate the impacts of obesity on the metabolic health of old mares as well as test the ability of diet supplementation with either a complex blend of nutrients designed to improve equine metabolism and gastrointestinal health or L-carnitine alone to mitigate negative effects of obesity. Mares (n = 19, 17.9 ± 3.7 years) were placed into one of three group: normal-weight (NW, n = 6), obese (OB, n = 7) or obese fed a complex diet supplement for 12 weeks (OBD, n = 6). After 12 weeks and completion of sample collections, OB mares received L-carnitine alone for an additional 6 weeks. Obesity in mares was significantly associated with insulin dysregulation, reduced muscle mitochondrial function, and decreased skeletal muscle oxidative capacity with greater ROS production when compared to NW. Obese mares fed the complex diet supplement had better insulin sensivity, greater cell lipid metabolism, and higher muscle oxidative capacity with reduced ROS production than OB. L-carnitine supplementation alone did not significantly alter insulin signaling, but improved lipid metabolism and muscle oxidative capacity with reduced ROS. In conclusion, obesity is associated with insulin dysregulation and altered skeletal muscle metabolism in older mares. However, dietary interventions are an effective strategy to improve metabolic status and skeletal muscle mitochondrial function in older mares.

Maternal pre-pregnancy BMI influences the associations between bisphenol and phthalate exposures and maternal weight changes and fat accumulation.

BACKGROUND: Bisphenols and phthalates are two classes of endocrine-disrupting chemicals (EDCs) thought to influence weight and adiposity. Limited research has investigated their influence on maternal weight changes, and no prior work has examined maternal fat mass. We examined the associations between exposure to these chemicals during pregnancy and multiple maternal weight and fat mass outcomes. METHODS: This study included a sample of 318 women enrolled in a Canadian prospective pregnancy cohort. Second trimester urinary concentrations of 2 bisphenols and 12 phthalate metabolites were quantified. Self-reported and measured maternal weights and measured skinfold thicknesses were used to calculate gestational weight gain, 3-months and 3- to 5-years postpartum weight retention, late pregnancy fat mass gain, total postpartum fat mass loss, and late postpartum fat mass retention. Adjusted robust regressions examined associations between chemicals and outcomes in the entire study population and sub-groups stratified by pre-pregnancy body mass index (BMI). Bayesian kernel machine regression examined chemical mixture effects. RESULTS: Among women with underweight or normal pre-pregnancy BMIs, MBzP was negatively associated with weight retention at 3- to 5-years postpartum (B = -0.04, 95%CI: -0.07, -0.01). Among women with overweight or obese pre-pregnancy BMIs, MEHP and MMP were positively associated with weight retention at 3-months and 3- to 5-years postpartum, respectively (B's = 0.12 to 0.63, 95%CIs: 0.02, 1.07). DEHP metabolites and MCNP were positively associated with late pregnancy fat mass gain and late postpartum fat mass retention (B's = 0.04 to 0.18, 95%CIs: 0.001, 0.32). Further, the mixture of EDCs was positively associated with late pregnancy fat mass gain. CONCLUSION: In this cohort, pre-pregnancy BMI was a key determinant of the associations between second trimester exposure to bisphenols and phthalates and maternal weight changes and fat accumulation. Investigations of underlying physiological mechanisms, windows of susceptibility, and impacts on maternal and infant health are needed.

Sex-Specific Effects of THRß Signaling on Metabolic Responses to High Fat Diet in Mice.

Thyroid hormone (TH) plays a crucial role in regulating the functions of both bone and adipose tissue. Given that TH exerts its cholesterol-lowering effects in hepatic tissue through the TH receptor-ß (TRß), we hypothesized that TRß agonist therapy using MGL3196 (MGL) would be effective in treating increased adiposity and bone loss in response to a 12-week high-fat diet (HFD) in adult C57BL/6J mice. Transcriptional and serum profiling revealed that HFD-induced leptin promoted weight gain in both males and females, but MGL only suppressed leptin induction and weight gain in males. In vitro studies suggest that estrogen suppresses MGL activity in adipocytes, indicating that estrogen might interfere with MGL-TRß function. Compared to systemic adiposity, HFD reduced bone mass in male but not female mice. Paradoxically, MGL treatment reversed macroscopic bone mineral density loss in appendicular bones, but micro-CT revealed that MGL exacerbated HFD-induced trabecular bone loss, and reduced bone strength. In studies on the mechanisms for HFD effects on bone, we found that HFD induced Rankl expression in male femurs that was blocked by MGL. By ex vivo assays, we found that RANKL indirectly represses osteoblast lineage allocation of osteoprogenitors by induction of inflammatory cytokines TNFα, IL-1ß, and CCL2. Finally, we found that MGL functions in both systemic adiposity and bone by nongenomic TRß signaling, as HFD-mediated phenotypes were not rescued in TRß147F knockout mice with normal genomic but defective nongenomic TRß signaling. Our findings demonstrate that the negative effects of HFD on body fat and bone phenotypes are impacted by MGL in a gender-specific manner.

Metformin treatment prevents experimental metabolic syndrome-induced femoral bone marrow adiposity in rats. / Tratamiento con metformina previene la adiposidad de la médula ósea femoral inducida por un síndrome metabólico experimental en ratas.

OBJECTIVE.: Motivation for the study. Most research supports a negative association between metabolic syndrome and bone health, although there is an overall lack of consensus. Therefore, there is a need for research in this area to develop a better understanding. Main findings. Metabolic syndrome induced by a fructose-rich diet increases the adipogenic predisposition of bone marrow progenitor cells and femoral medullary adiposity in rats. Furthermore, this can be partially prevented by co-treatment with metformin. Implications. Experimental metabolic syndrome has negative effects on bone tissue and can be prevented by oral treatment with metformin as a normoglycemic drug. To determine the effect of metformin (MET) treatment on adipogenic predisposition of bone marrow progenitor cells (BMPC), bone marrow adiposity and bone biomechanical properties. MATERIALS AND METHODS.: 20 young adult male Wistar rats were sorted into four groups. Each of the groups received the following in drinking water: 100% water (C); 20% fructose (F); metformin 100 mg/kg wt/day (M); or fructose plus metformin (FM). After five weeks the animals were sacrificed. Both humeri were dissected to obtain BMPC, and both femurs were dissected to evaluate medullary adiposity (histomorphometry) and biomechanical properties (3-point bending). BMPC were cultured in vitro in adipogenic medium to evaluate RUNX2, PPAR-γ and RAGE expression by RT-PCR, lipase activity and triglyceride accumulation. RESULTS.: The fructose-rich diet (group F) caused an increase in both triglycerides in vitro, and medullary adiposity in vivo; being partially or totally prevented by co-treatment with metformin (group FM). No differences were found in femoral biomechanical tests in vivo, nor in lipase activity and RUNX2/PPAR-γ ratio in vitro. DRF increased RAGE expression in BMPC, being prevented by co-treatment with MET. CONCLUSIONS.: Metabolic syndrome induced by a fructose-rich diet increases femoral medullary adiposity and, in part, the adipogenic predisposition of BMPC. In turn, this can be totally or partially prevented by oral co-treatment with MET.

OBJETIVO.: Motivación para realizar el estudio. La mayoría de las investigaciones respaldan una asociación negativa entre el síndrome metabólico y la salud ósea, aunque existe una falta de consenso general. Por lo tanto, es necesario realizar investigaciones en esta área que permitan desarrollar un mejor conocimiento. Principales hallazgos. El síndrome metabólico inducido por una dieta rica en fructosa incrementa la predisposición adipogénica de células progenitoras de médula ósea y la adiposidad medular femoral en ratas. Además, esto puede prevenirse parcialmente mediante un co-tratamiento con metformina. Implicancias. El síndrome metabólico experimental posee efectos negativos sobre el tejido óseo, pudiendo ser prevenidos mediante un tratamiento oral de metformina como fármaco normoglucemiante. Determinar el efecto de un tratamiento con metformina (MET) sobre la predisposición adipogénica de células progenitoras de médula ósea (CPMO), adiposidad de la médula ósea y propiedades biomecánicas óseas. MATERIALES Y MÉTODOS.: 20 ratas Wistar machos adultos jóvenes fueron separados en cuatro grupos, recibiendo en agua de bebida: 100% agua (C); 20% de fructosa (F); metformina 100 mg/kg peso/día (M); o fructosa más metformina (FM). Tras cinco semanas se sacrificaron los animales, se diseccionaron ambos húmeros para obtener CPMO, y ambos fémures para evaluar adiposidad medular (histomorfometría) y propiedades biomecánicas (flexión a 3 puntos). Las CPMO se cultivaron in vitro en medio adipogénico para evaluar expresión de RUNX2, PPAR-γ y RAGE por RT-PCR, actividad de lipasa y acumulación de triglicéridos. RESULTADOS.: La dieta rica en fructosa (grupo F) produjo un aumento tanto de triglicéridos in vitro, como de la adiposidad medular in vivo; siendo parcial o totalmente prevenido por un co-tratamiento con metformina (grupo FM). No se observaron diferencias en las pruebas biomecánicas femorales in vivo, ni en actividad de lipasa y relación RUNX2/PPAR-γ in vitro. La DRF aumentó la expresión de RAGE en CPMO, siendo prevenido por co-tratamiento con MET. CONCLUSIONES.: El síndrome metabólico inducido por una dieta rica en fructosa aumenta la adiposidad medular femoral y, en parte, la predisposición adipogénica de las CPMO. A su vez, esto puede ser prevenido total o parcialmente por un co-tratamiento oral con MET.

Transgenic female mice producing trans 10, cis 12-conjugated linoleic acid present excessive prostaglandin E2, adrenaline, corticosterone, glucagon, and FGF21.

Dietary trans 10, cis 12-conjugated linoleic acid (t10c12-CLA) is a potential candidate in anti-obesity trials. A transgenic mouse was previously successfully established to determine the anti-obesity properties of t10c12-CLA in male mice that could produce endogenous t10c12-CLA. To test whether there is a different impact of t10c12-CLA on lipid metabolism in both sexes, this study investigated the adiposity and metabolic profiles of female Pai mice that exhibited a dose-dependent expression of foreign Pai gene and a shift of t10c12-CLA content in tested tissues. Compared to their gender-match wild-type littermates, Pai mice had no fat reduction but exhibited enhanced lipolysis and thermogenesis by phosphorylated hormone-sensitive lipase and up-regulating uncoupling proteins in brown adipose tissue. Simultaneously, Pai mice showed hepatic steatosis and hypertriglyceridemia by decreasing gene expression involved in lipid and glucose metabolism. Further investigations revealed that t10c10-CLA induced excessive prostaglandin E2, adrenaline, corticosterone, glucagon and inflammatory factors in a dose-dependent manner, resulting in less heat release and oxygen consumption in Pai mice. Moreover, fibroblast growth factor 21 overproduction only in monoallelic Pai/wt mice indicates that it was sensitive to low doses of t10c12-CLA. These results suggest that chronic t10c12-CLA has system-wide effects on female health via synergistic actions of various hormones.

AN698/40746067 suppresses bone marrow adiposity to ameliorate hyperlipidemia-induced osteoporosis through targeted inhibition of ENTR1.

Hyperlipidemia-induced osteoporosis is marked by increased bone marrow adiposity, and treatment with statins for hyperlipidemia often leads to new-onset osteoporosis. Endosome-associated trafficking regulator 1 (ENTR1) has been found to interact with different proteins in pathophysiology, but its exact role in adipogenesis is not yet understood. This research aimed to explore the role of ENTR1 in adipogenesis and to discover a new small molecule that targets ENTR1 for evaluating its effectiveness in treating hyperlipidemia-induced osteoporosis. We found that ENTR1 expression increased during the adipogenesis of bone marrow mesenchymal cells (BMSCs). ENTR1 gain- and loss-of-function assays significantly enhanced lipid droplets formation. Mechanistically, ENTR1 binds peroxisome proliferator-activated receptor γ (PPARγ) and enhances its expression, thereby elevating adipogenic markers including C/EBPα and LDLR. Therapeutically, AN698/40746067 attenuated adipogenesis by targeting ENTR1 to suppress PPARγ. In vivo, AN698/40746067 reduced bone marrow adiposity and bone loss, as well as prevented lipogenesis-related obesity, inflammation, steatohepatitis, and abnormal serum lipid levels during hyperlipidemia. Together, these findings suggest that ENTR1 facilitates adipogenesis by PPARγ involved in BMSCs' differentiation, and targeted inhibition of ENTR1 by AN698/40746067 may offer a promising therapy for addressing lipogenesis-related challenges and alleviating osteoporosis following hyperlipidemia.

Free fatty acid receptor 4 (FFA4) activation attenuates obese asthma by suppressing adiposity and resolving metaflammation.

Obese asthma is recognized to have different asthma phenotypes. N-3 polyunsaturated fatty acids (PUFAs) have shown beneficial effects in obesity and metabolic syndrome. Free fatty acid receptor 4 (FFA4, also known as GPR120) is a receptor for n-3 PUFAs. In the present study, we investigated whether FFA4 activation ameliorates high-fat diet (HFD)-induced obese asthma. We investigated whether FFA4 activation ameliorates obese asthma using an FFA4 agonist, compound A (CpdA), in combination with FFA4 wild-type (WT) and knock-out (KO) mice. Administration of an FFA4 agonist, compound A (CpdA, 30 mg/kg), suppressed HFD-induced weight gain, adiposity, and airway hypersensitivity (AHR), and increased immune cell infiltration in an FFA4-dependent manner. Histological analysis revealed that CpdA treatment suppressed HFD-induced mucus hypersecretion, inflammation, and fibrosis in an FFA4-dependent manner. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) showed an HFD-induced increase in the mRNA levels of pro-inflammatory cytokines in the lungs and gonadal white adipose tissue, whereas CpdA inhibited this increase in an FFA4-dependent manner. In the fluorescence-activated cell sorting (FACS) analysis, HFD induced an increase in the lung innate lymphoid cells (ILC) ILC1, ILC2, and ILC3; however, CpdA reversed this increase. In addition, HFD induced an increase in the pro-inflammatory M1 macrophage population and a decrease in the anti-inflammatory M2 macrophage population in the lungs, whereas CpdA treatment reversed these changes. The present study suggests that FFA4 activation may have therapeutic potential in obese asthma.

Association of serum sclerostin levels with marrow adiposity in postmenopausal women with glucocorticoid-induced osteoporosis.

BACKGROUND: Glucocorticoids and sclerostin act as inhibitors of the Wnt signaling pathway, thereby hindering bone formation. Given the pathway's intricate association with mesenchymal stem cells, the hypothesis suggests that heightened sclerostin levels may be intricately linked to an augmentation in marrow adiposity induced by glucocorticoids. This study endeavored to delve into the nuanced relationship between circulating sclerostin and bone marrow adipose tissue in postmenopausal women grappling with glucocorticoid-induced osteoporosis (GIO). METHODS: In this cross-sectional study, 103 patients with autoimmune-associated diseases underwent glucocorticoid treatment, boasting an average age of 61.3 years (standard deviation 7.1 years). The investigation encompassed a thorough assessment, incorporating medical history, anthropometric data, biochemical analysis, and dual-energy X-ray absorptiometry measurements of lumbar and femoral bone mineral density (BMD). Osteoporosis criteria were established at a T-score of -2.5 or lower. Additionally, MR spectroscopy quantified the vertebral marrow fat fraction. RESULTS: BMD at the femoral neck, total hip, and lumbar spine showcased an inverse correlation with marrow fat fraction (r = -0.511 to - 0.647, P < 0.001). Serum sclerostin levels exhibited a positive correlation with BMD at various skeletal sites (r = 0.476 to 0.589, P < 0.001). A noteworthy correlation emerged between circulating sclerostin and marrow fat fraction at the lumbar spine (r = -0.731, 95% CI, -0.810 to -0.627, P < 0.001). Multivariate analysis brought to light that vertebral marrow fat fraction significantly contributed to sclerostin serum concentrations (standardized regression coefficient ß = 0.462, P < 0.001). Even after adjusting for age, body mass index, physical activity, renal function, BMD, and the duration and doses of glucocorticoid treatment, serum sclerostin levels maintained a significant correlation with marrow fat fraction. CONCLUSIONS: Circulating sclerostin levels exhibited a noteworthy association with marrow adiposity in postmenopausal women grappling with GIO.

Combined supplementation with hesperidin, phytosterols and curcumin decreases adiposity and improves metabolic health in ovariectomized rats.

In recent years many women have looked for alternative therapies to address menopause. Hesperidin, phytosterols and curcumin are bioactive compounds that can ameliorate some cardiovascular risk factors associated with menopause, although there are no data concerning the effects of their combined supplementation. We used ovariectomized (OVX) rats, a postmenopausal model with oestrogen deficiency, to evaluate whether supplementation with a multi-ingredient (MI) including hesperidin, phytosterols and curcumin for 57 days would display beneficial effects against fat mass accretion and metabolic disturbances associated with menopause. Twenty OVX rats were orally supplemented with either MI (OVX-MI) or vehicle (OVX). Furthermore, 10 OVX rats orally received the vehicle along with subcutaneous injections of 17ß-oestradiol biweekly (OVX-E2), whereas 10 rats were sham operated and received oral and injected vehicles (control group; SH). MI supplementation partly counteracted the fat mass accretion observed in OVX animals, which was evidenced by decreased total fat mass, adiposity index, the weight of retroperitoneal, inguinal and mesenteric white adipose tissue (MWAT) depots and MWAT adipocyte hypertrophy. These effects were accompanied by a significant decrease in the circulating levels of leptin and the mRNA levels of the fatty acid uptake-related genes Lpl and Cd36 in MWAT. These results were very similar to those observed in OVX-E2 animals. OVX-MI rats also displayed a higher lean body mass, lean/fat mass ratio, adiponectin-to-leptin ratio and insulin sensitivity than their OVX counterparts. Our findings can pave the way for using this MI formulation as an alternative therapy to manage obesity and to improve the cardiometabolic health of menopausal women.

Influence of glucagon-like peptide-1 receptor agonists on fat accumulation in patients with diabetes mellitus and non-alcoholic fatty liver disease or obesity: A systematic review and meta-analysis of randomized control trials.

AIM: This systematic review and meta-analysis aimed to comprehensively evaluate the impact of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in individuals with diabetes mellitus and non-alcoholic fatty liver disease (NAFLD) or obesity. METHODS: A search of PubMed, Embase, and Web of Science until October 2023 identified 13 Randomized Controlled Trials (RCTs) meeting the inclusion criteria. Bias risk was assessed using the Cochrane risk-of-bias instrument. Statistical analysis utilized standard mean differences (SMD) in Review Manager 5.4. Heterogeneity and publication bias were assessed. This study used the protocol registered with the Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY2023110020). RESULTS: GLP-1RA treatment significantly reduced VAT (SMD -0.55, 95 % CI [-0.90, -0.19]), SAT (SMD -0.59, 95 % CI [-0.99, -0.19]), body weight (SMD -1.07, 95 % CI [-1.67, -0.47]), and body mass index (BMI) (SMD -1.10, 95 % CI [-1.74, -0.47]) compared to controls. Heterogeneity was observed for VAT (I2 = 79 %, P < 0.01), SAT (I2 = 73 %, P < 0.01), body weight (I2 = 82 %, P < 0.01), and BMI (I2 = 82 %, P < 0.01). No publication bias was detected for VAT (P = 0.57) and SAT (P = 0.18). GLP-1RA treatment improved fasting blood glucose (FBG), postprandial glucose (PPG), hemoglobin A1c (HbA1c), Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and fibrosis-4 (FIB-4). CONCLUSIONS: This meta-analysis highlights GLP-1RAs' potential to reduce fat accumulation, body weight, and BMI and improve glycemic control in individuals with diabetes mellitus and NAFLD or obesity. These findings supported using GLP-1RAs as promising therapeutic agents to address abnormal adipose tissue distribution and metabolic dysfunction.

Effects of beef fat enriched with trans vaccenic acid and cis9, trans11-CLA on glucose homoeostasis and hepatic lipid accumulation in high-fat diet-induced obese mice.

Trans vaccenic acid (TVA, trans11-18 : 1) and cis9, trans11-CLA (also known as rumenic acid; RA) have received widespread attention as potentially beneficial trans-FA due to their putative health benefits, including anti-diabetic properties. The objective of this study was to determine the effects of beef fat naturally enriched with TVA and RA on parameters related to glucose homoeostasis and associated metabolic markers in diet-induced obese (DIO) mice. Thirty-six male C57BL/6J mice (8 weeks old) were fed for 19 weeks with either a control low-fat diet (CLF), a control high-fat diet (CHF), or a TVA+RA-enriched high-fat diet (EHF). Compared with CLF, feeding either CHF or EHF resulted in adverse metabolic outcomes associated with high-fat diets, including adiposity, impaired glucose control and hepatic steatosis. However, the EHF diet induced a significantly higher liver weight TAG content and elevated plasma alanine transaminase levels compared with the CHF diet. Collectively, the findings from this study suggest that EHF does not improve glucose tolerance and worsens liver steatosis in DIO mice. However, the adverse effects of EHF on the liver could be in part related to the presence of other trans-FA in the enriched beef fat.

Effects of prenatal THC vapor exposure on body weight, glucose metabolism, and feeding behaviors in chow and high-fat diet fed rats.

BACKGROUND: 4-20% of people report using cannabis during pregnancy, thereby it is essential to assess the associated risks. There is some evidence that prenatal cannabis exposure (PCE) may be associated with increased risk for developing of obesity and diabetes later in life, however this has not been well explored under controlled conditions. The aim of this study was to use a translational THC vapor model in rodents to characterize the effects of PCE on adiposity, glucose metabolism, and feeding patterns in adulthood, with focus on potential sex differences. METHODS: Pregnant Sprague Dawley rats were exposed to vaporized THC (100 mg/ml) or control (polyethylene glycol vehicle) across the entire gestational period. Adult offspring from PCE (n = 24) or control (n = 24) litters were subjected to measures of adiposity, glucose metabolism and feeding behavior. Rats were then placed onto special diets (60% high-fat diet [HFD] or control 10% low fat diet [LFD]) for 4-months, then re-subjected to adiposity, glucose metabolism and feeding behavior measurements. RESULTS: PCE did not influence maternal weight or food consumption but was associated with transient decreased pup weight. PCE did not initially influence bodyweight or adiposity, but PCE did significantly reduce the rate of bodyweight gain when on HFD/LFD, regardless of which diet. Further, PCE had complex effects on glucose metabolism and feeding behavior that were both sex and diet dependent. No effects of PCE were found on plasma leptin or insulin, or white adipose tissue mass. CONCLUSIONS: PCE may not promote obesity development but may increase risk for diabetes and abnormal eating habits under certain biological and environmental conditions. Overall, this data enhances current understanding of the potential impacts of PCE.

Stem cell secretome treatment improves whole-body metabolism, reduces adiposity, and promotes skeletal muscle function in aged mice.

Aging coincides with the progressive loss of muscle mass and strength, increased adiposity, and diminished physical function. Accordingly, interventions aimed at improving muscle, metabolic, and/or physical health are of interest to mitigate the adverse effects of aging. In this study, we tested a stem cell secretome product, which contains extracellular vesicles and growth, cytoskeletal remodeling, and immunomodulatory factors. We examined the effects of 4 weeks of 2×/week unilateral intramuscular secretome injections (quadriceps) in ambulatory aged male C57BL/6 mice (22-24 months) compared to saline-injected aged-matched controls. Secretome delivery substantially increased whole-body lean mass and decreased fat mass, corresponding to higher myofiber cross-sectional area and smaller adipocyte size, respectively. Secretome-treated mice also had greater whole-body physical function (grip strength and rotarod performance) and had higher energy expenditure and physical activity levels compared to control mice. Furthermore, secretome-treated mice had greater skeletal muscle Pax7+ cell abundance, capillary density, collagen IV turnover, reduced intramuscular lipids, and greater Akt and hormone sensitive lipase phosphorylation in adipose tissue. Finally, secretome treatment in vitro directly enhanced muscle cell growth and IL-6 production, and in adipocytes, it reduced lipid content and improved insulin sensitivity. Moreover, indirect treatment with secretome-treated myotube culture media also enhanced muscle cell growth and adipocyte size reduction. Together, these data suggest that intramuscular treatment with a stem cell secretome improves whole-body metabolism, physical function, and remodels skeletal muscle and adipose tissue in aged mice.

The effects of ghrelin and LEAP-2 in energy homeostasis are modulated by thermoneutrality, high-fat diet and aging.

PURPOSE: Liver-expressed antimicrobial peptide 2 (LEAP-2) has been recently identified as the endogenous non-competitive allosteric antagonist of the growth hormone secretagogue receptor 1a (GHSR1a). In rodents, LEAP-2 blunts ghrelin-induced feeding and its plasma levels are modulated in response to nutritional status, being decreased upon fasting and increased in high-fat diet (HFD) fed mice. Clinical data support the regulation of circulating LEAP-2 by nutrient availability in humans. In this work, our primary objective was to examine the chronic effects of ghrelin and LEAP-2 administration on food intake, adiposity, and energy expenditure in young mice subjected to standard and HFD at both room temperature and at thermoneutrality. Furthermore, we aimed to assess the impact of these two hormones on aging mice. RESULTS: Our results indicate that LEAP-2 produces a significant decrease of body weight and adiposity, an increase in energy expenditure, and activation of the thermogenic program in white and brown adipose tissue depots. However, this effect is not maintained under HFD or under thermoneutral conditions and is only partially observed in aging mice. CONCLUSION: In summary our studies describe the central effects of LEAP-2 within distinct experimental contexts, and contribute to the comprehension of LEAP-2's role in energy metabolism.

An exercise-inducible metabolite that suppresses feeding and obesity.

Exercise confers protection against obesity, type 2 diabetes and other cardiometabolic diseases1-5. However, the molecular and cellular mechanisms that mediate the metabolic benefits of physical activity remain unclear6. Here we show that exercise stimulates the production of N-lactoyl-phenylalanine (Lac-Phe), a blood-borne signalling metabolite that suppresses feeding and obesity. The biosynthesis of Lac-Phe from lactate and phenylalanine occurs in CNDP2+ cells, including macrophages, monocytes and other immune and epithelial cells localized to diverse organs. In diet-induced obese mice, pharmacological-mediated increases in Lac-Phe reduces food intake without affecting movement or energy expenditure. Chronic administration of Lac-Phe decreases adiposity and body weight and improves glucose homeostasis. Conversely, genetic ablation of Lac-Phe biosynthesis in mice increases food intake and obesity following exercise training. Last, large activity-inducible increases in circulating Lac-Phe are also observed in humans and racehorses, establishing this metabolite as a molecular effector associated with physical activity across multiple activity modalities and mammalian species. These data define a conserved exercise-inducible metabolite that controls food intake and influences systemic energy balance.

γ Peptide Nucleic Acid-Based miR-122 Inhibition Rescues Vascular Endothelial Dysfunction in Mice Fed a High-Fat Diet.

The blood levels of microRNA-122 (miR-122) is associated with the severity of cardiovascular disorders, and targeting it with efficient and safer miR inhibitors could be a promising approach. Here, we report the generation of a γ-peptide nucleic acid (γPNA)-based miR-122 inhibitor (γP-122-I) that rescues vascular endothelial dysfunction in mice fed a high-fat diet. We synthesized diethylene glycol-containing γP-122-I and found that its systemic administration counteracted high-fat diet (HFD)-feeding-associated increase in blood and aortic miR-122 levels, impaired endothelial function, and reduced glycemic control. A comprehensive safety analysis established that γP-122-I affects neither the complete blood count nor biochemical tests of liver and kidney functions during acute exposure. In addition, long-term exposure to γP-122-I did not change the overall adiposity, or histology of the kidney, liver, and heart. Thus, γP-122-I rescues endothelial dysfunction without any evidence of toxicity in vivo and demonstrates the suitability of γPNA technology in generating efficient and safer miR inhibitors.

The Potential to Fight Obesity with Adipogenesis Modulating Compounds.

Obesity is an increasingly severe public health problem, which brings huge social and economic burdens. Increased body adiposity in obesity is not only tightly associated with type 2 diabetes, but also significantly increases the risks of other chronic diseases including cardiovascular diseases, fatty liver diseases and cancers. Adipogenesis describes the process of the differentiation and maturation of adipocytes, which accumulate in distributed adipose tissue at various sites in the body. The major functions of white adipocytes are to store energy as fat during periods when energy intake exceeds expenditure and to mobilize this stored fuel when energy expenditure exceeds intake. Brown/beige adipocytes contribute to non-shivering thermogenesis upon cold exposure and adrenergic stimulation, and thereby promote energy consumption. The imbalance of energy intake and expenditure causes obesity. Recent interest in epigenetics and signaling pathways has utilized small molecule tools aimed at modifying obesity-specific gene expression. In this review, we discuss compounds with adipogenesis-related signaling pathways and epigenetic modulating properties that have been identified as potential therapeutic agents which cast some light on the future treatment of obesity.