Effect of adiposectomy and feeding level on FSH‐induced testicular growth in male lizards Anolis carolinensis (Reptilia: Iguanidae)

Background & AimsThis was a double-blind 12-week extension of a randomized, placebo-controlled, 12-week trial of pemvidutide, a glucagon-like peptide-1/glucagon dual receptor agonist, in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD).MethodsCompleters of a double-blind trial of pemvidutide in MASLD, who were previously randomized 1:1:1:1 to pemvidutide at 1.2 mg, 1.8 mg, or 2.4 mg, or placebo administered subcutaneously once weekly for 12 weeks, were offered an additional 12 weeks of treatment at their originally assigned dose for a total of 24 weeks of treatment. Participants were stratified by the presence or absence of type 2 diabetes mellitus (T2DM). The primary efficacy endpoint was relative reduction (%) from baseline in liver fat content by magnetic resonance imaging-proton density fat fraction after 24 weeks of treatment.ResultsThere were 64 participants in the extension trial. Baseline mean values for BMI and liver fat content were 36.7 kg/m2 and 22.2%; 26.6% of participants had T2DM. After 24 weeks of treatment, pemvidutide achieved relative reductions in liver fat content from baseline of 56.3%, 75.2%, and 76.4% for the pemvidutide 1.2 mg, 1.8 mg, and 2.4 mg groups respectively, vs. 14.0% for placebo (p <0.001 vs. placebo, all treatment groups), with 84.6% of participants achieving 50% reductions in liver fat content and 53.8% achieving normalization (≤5% liver fat content) at the 1.8 mg dose. Body weight was also reduced by 6.2% (p <0.001 vs. placebo) over 24 weeks of treatment. Pemvidutide was well-tolerated at all doses, with low incidences of side effects.ConclusionsIn individuals with MASLD, 24 weeks of pemvidutide treatment resulted in significant reductions in liver fat content and body weight that further improved upon the effects observed at 12 weeks.Impact and implicationsOverweight and obesity are strongly associated with metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASH), as the excess liver fat associated with obesity is a known driver of these conditions. Glucagon-like peptide-1 receptor (GLP-1R) agonists elicit weight loss through centrally and peripherally mediated effects on appetite, whereas G-coupled glucagon receptor (GCGR) agonists act directly on the liver to stimulate fatty acid oxidation and inhibit lipogenesis, providing a more potent mechanism for reducing liver fat content than weight loss alone. We previously showed that once-weekly treatment with pemvidutide, a dual GLP-1R/GCGR agonist, significantly reduced liver fat content, hepatic inflammatory activity, and body weight over 12 weeks. The current trial demonstrates that continued treatment with pemvidutide further improves these clinical markers of MASH.Clinical Trials RegistrationThe study is registered at ClinicalTrials.gov (NCT05292911).

This Month in Gastroenterology

We measured liver fat content by 3-Tesla magnetic resonance spectroscopy (MRS) in 34 non- to mild obese Japanese subjects with type 2 diabetes, who were not complicated with any liver diseases including clinical fatty liver (liver/spleen ratio of computed tomography [CT] < 0.9) and were not being treated with oral hypoglycemic agents, insulin, or lipid-lowering agents, and analyzed the relationship between liver fat content and body composition and plasma metabolite. The liver fat content is significantly correlated with variables relating to obesity (body mass index [BMI], body weight, fat mass, waist to hip ratio, visceral fat area, subcutaneous fat area, and serum triglyceride), insulin resistance (fasting plasma insulin and homeostasis model assessment of insulin resistance [HOMA-IR]), adipocytokines (serum plasminogen activator inhibitor-1 [PAI-1] and leptin), and serum cholinesterase, but not CT liver/spleen ratio, which is correlated only with fasting plasma glucose, BMI, and HOMA-IR. Multiple regression analysis revealed that the liver fat content is independently associated with serum PAI-1 level (p < 0.001) and BMI (p < 0.05), but not visceral fat area. MRS is a more sensitive method for quantifying liver fat content than CT in type 2 diabetic subjects with non- to mild obesity and without clinical fatty liver.

Ectopic accumulation of lipids in nonadipose tissues plays a primary role in the pathogenesis of type 2 diabetes mellitus (T2DM). This study was to examine the effects of exenatide, insulin, and pioglitazone on liver fat content and body fat distributions in T2DM. Thirty-three drug-naive T2DM patients (age 52.7±1.7years, HbA1c 8.7±0.2%, body mass index 24.5±0.5kg/m(2)) were randomized into exenatide, insulin, or pioglitazone for 6months. Intrahepatic fat (IHF), visceral fat (VF), and subcutaneous fat (SF) were measured using proton nuclear magnetic resonance spectroscopy. Plasma tumor necrosis factor α (TNFα) and adiponectin were assayed by ELISA. HbA1c declined significantly in all three groups. Body weight, waist, and serum triglycerides decreased with exenatide. After interventions, IHF significantly reduced with three treatments (exenatide Δ=-68%, insulin Δ=-58%, pioglitazone Δ=-49%). Exenatide reduced VF (Δ=-36%) and SF (Δ=-13%), and pioglitazone decreased VF (Δ=-30%) with no impact on SF, whereas insulin had no impact on VF or SF. Levels of TNFα (exenatide/insulin/pioglitazone) decreased, and levels of adiponectin (exenatide/pioglitazone) increased. Analysis showed that ΔIHF correlated with ΔHbA1c and Δweight. Besides, ΔIHF correlated with Δtriglycerides and ΔTNFα, but the correlations fell short of significance after BMI adjustment. By linear regression analysis, ΔHbA1c alone explained 41.5% of the variance of ΔIHF, and ΔHbA1c+Δweight explained 57.6% of the variance. Liver fat content can be significantly reduced irrespective of using exenatide, insulin, and pioglitazone. Early glycaemic control plays an important role in slowing progression of fatty liver in T2DM.

To investigate the effects of Xanthigen (brown marine algae fucoxanthin + pomegranate seed oil (PSO)) on body weight, body fat, liver lipids, and blood biochemistry; and Xanthigen and its individual components on resting energy expenditure (REE) in obese, non-diabetic female volunteers with non-alcoholic fatty liver disease (NAFLD) and normal liver fat (NLF) content. Sixteen-week, double-blind, randomized, placebo-controlled study. Food record data, body composition, REE (only 41 volunteers with NAFLD) and blood sample analysis were assessed weekly for 16 weeks in 151 non-diabetic, obese premenopausal women with liver fat content above 11% (NAFLD) n = 113, and below 6.5% (NLF) n = 38. Xanthigen-600/2.4 mg (300 mg PSO + 300 mg brown seaweed extract containing 2.4 mg fucoxanthin) resulted in statistically significant reduction of body weight (5.5 +/- 1.4 kg NAFLD group and 4.9 +/- 1.2 kg NLF group, p < 0.05), waist circumference (NAFLD group only), body (3.5 +/- 1.9 kg NAFLD group, p < 0.001; 3.6 +/- 0.7 kg NLF group, p < 0.05) and liver fat content, liver enzymes (NAFLD group only), serum triglycerides and C-reactive protein. Weight loss and reduction in body and liver fat content occurred earlier in patients with NLF than in patients with NAFLD. Fucoxanthin (> 2.4 mg) and Xanthigen-400/1.6 mg (200 mg PSO + 200 mg brown seaweed extract containing 1.6 mg fucoxanthin) significantly increased REE in NAFLD subjects compared to placebo. Xanthigen promoted weight loss, reduced body and liver fat content, and improved liver function tests in obese non-diabetic women. Xanthigen and Fucoxanthin also increased REE. This product may be considered a promising food supplement in the management of obesity.

Laparoscopic adjustable gastric banding (LAGB) requires surgical access to the gastroesophageal junction, which may be compromised by the enlarged, fatty liver that is frequently encountered in the obese. Liver size appears reduced and surgical access improved following preoperative weight loss with Optifast Very Low Calorie Diet (VLCD). The aim of this study was to assess the effects of 6 weeks Optifast VLCD on liver volume and fat content. 18 morbidly obese subjects underwent magnetic resonance imaging and spectroscopy to measure liver size and fat content before and after intensive treatment with Optifast VLCD for 6 weeks. All subjects completing 6 weeks Optifast VLCD lost weight. Body weight and BMI (median [interquartile range]) reduced from 119.7 [111.9-131.3] kg and 44 [40-51] kg/m(2) respectively, to 110.6 [98.0124.5] kg and 40 [36-47] kg/m(2), P<0.001. Median excess weight loss (EWL) was 15.1 [9.6-21.1]%. Baseline liver volume and fat content were related (r=0.633, P=0.005). After 6 weeks Optifast VLCD, there was a 14.7% reduction in mean liver volume (P<0.001) and a 43% reduction in mean liver fat (P=0.016). The change in liver volume was predicted by the change in the liver fat (r = 0.610, P=0.012). This study has demonstrated that a 6 week diet with Optifast VLCD results in significant related reductions in liver size and liver fat content. This suggests that the reduction in liver volume is due to loss of fat. The reduction in liver fat and volume likely accounts for the perceived improved operability in patients undergoing LAGB.

The prevalence of obesity in the United States and the world has risen to epidemic/pandemic proportions. This increase has occurred despite great efforts by healthcare providers and consumers alike to improve the health-related behaviors of the population and a tremendous push from the scientific community to better understand the pathophysiology of obesity. This epidemic is all the more concerning given the clear association between excess adiposity and adverse health consequences such as cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). The risks associated with overweight/obesity are primarily related to the deposition of adipose tissue, which leads to excess adiposity or body fatness. Furthermore, weight loss, specifically loss of body fat, is associated with improvement in obesity-related comorbidities. Before weight loss interventions can be recommended, however, patients must be assessed for their adiposity-related risk. Unfortunately, healthcare providers and systems have not done a good job of assessing for excess adiposity even in its simplest form, such as measuring body mass index (BMI). It is for these reasons that we must emphasize the importance of assessing adiposity in clinical practices. Although it can be argued that the entire population should be targeted as an important public health issue with a goal of prevention of weight gain and obesity, there are currently so many “at risk” individuals that simple strategies to identify and treat those individuals are necessary. We must identify those individuals at highest risk of comorbidities in order to identify those who might benefit the most from aggressive weight management. This scientific statement will first briefly review the epidemiology of obesity and its related comorbidities, supporting the need for improved assessment of adiposity in daily clinical practice. This will be followed by a discussion of some of the challenges and issues associated with assessing adiposity and then by a review …

Survodutide is a glucagon/glucagon-like peptide-1 receptor dual agonist in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). We investigated the pharmacokinetic and safety profile of survodutide in people with cirrhosis. This multinational, non-randomized, open-label, phase I clinical trial initially evaluated a single subcutaneous dose of survodutide 0.3mg in people with Child-Pugh class A, B or C cirrhosis and healthy individuals with or without overweight/obesity matched for age, sex, and weight; the primary endpoints were the area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) and maximal plasma concentration (Cmax). Subsequently, people with overweight/obesity with or without cirrhosis (Child-Pugh class A or B) received once-weekly subcutaneous doses escalated from 0.3mg to 6.0mg over 24 weeks then maintained for 4 weeks; the primary endpoint was drug-related treatment-emergent adverse events, with MASH/cirrhosis-related endpoints explored. In the single-dose cohorts (n= 41), mean AUC0-∞ and Cmax were similar in those with cirrhosis compared with healthy individuals (90% CIs for adjusted geometric mean ratios spanned 1). Drug-related adverse events occurred in 25.0% of healthy individuals and ≤25.0% of those with cirrhosis after single doses, and 82.4% and 87.5%, respectively, of the multiple-dose cohorts (n= 41) over 28 weeks. Liver fat content, liver stiffness, liver volume, body weight, and other hepatic and metabolic disease markers were generally reduced after 28 weeks of survodutide treatment. Survodutide is generally tolerable in people with compensated or decompensated cirrhosis, does not require pharmacokinetic-related dose adjustment, and may improve liver-related non-invasive tests, supporting its investigation for MASH-related cirrhosis. Survodutide is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH), which causes cirrhosis in ∼20% of cases. This trial delineates the pharmacokinetic and safety profile of survodutide in people with compensated or decompensated cirrhosis, and revealed associated reductions in liver fat content, markers of liver fibrosis and body weight. These findings have potential relevance for people with MASH-including those with decompensated cirrhosis, who are usually excluded from clinical trials of investigational drugs. Based on this study, further investigation of survodutide for MASH-related cirrhosis is warranted. NCT05296733.

Nonalcoholic fatty liver disease is very frequent in type 2 diabetes, with increased risk of further development of liver fibrosis. Animal studies have shown that GLP-1 receptor agonists may reduce liver lipogenesis. However, data in humans are scarce. To study the effect of liraglutide 1.2 mg/d on liver fat content (LFC) in patients with uncontrolled type 2 diabetes and to evaluate the factors potentially associated with liraglutide-induced modification of LFC. LFC was measured by proton magnetic resonance spectroscopy before and after 6 months of liraglutide treatment in 68 patients with uncontrolled type 2 diabetes mellitus. Liraglutide 1.2 mg/d. Change in LFC. Treatment with liraglutide was associated with a significant decrease in body weight, HbA1C, and a marked relative reduction in LFC of 31% (P < 0.0001). No significant modification of LFC was observed in a parallel group of patients 6 months after intensification of the antidiabetic treatment with insulin. The reduction in LFC and body weight were highly correlated (r = 0.490; P < 0.0001). In multivariate analysis, the reduction in LFC was independently associated with baseline LFC (P < 0.0001), age (P = 0.010), and reduction in body weight (P < 0.0001), triglycerides (P = 0.019), and HbA1c (P = 0.034). In the patients who had no significant decrease in body weight, no significant reduction in LFC was observed. Six months of treatment with liraglutide 1.2 mg/d significantly reduced LFC in patients with inadequately controlled type 2 diabetes and this effect was mainly driven by body weight reduction. Further studies are needed to confirm that this reduction in LFC may significantly reduce fibrosis progression.

The aim of this study was to investigate the associations between liver fat content (LFC), sedentary behaviour (SB), physical activity (PA), fitness, diet, body composition, and cardiometabolic risk factors in adults with metabolic syndrome. A total of 44 sedentary adults (mean age 58 [SD 7] years; 25 women) with overweight or obesity participated. LFC was assessed with magnetic resonance spectroscopy and imaging, SB and PA with hip-worn accelerometers (26 [SD 3] days), fitness by maximal bicycle ergometry, body composition by air displacement plethysmography and nutrient intake by 4-day food diaries. LFC was not independently associated with SB, PA or fitness. Adjusted for sex and age, LFC was associated with body fat%, body mass index, waist circumference, triglycerides, alanine aminotransferase, and with insulin resistance markers. There was and inverse association between LFC and daily protein intake, which persisted after further adjusment with body fat%. LFC is positively associated with body adiposity and cardiometabolic risk factors, and inversely with daily protein intake. SB, habitual PA or fitness are not independent modulators of LFC. However, as PA is an essential component of healthy lifestyle, it may contribute to liver health indirectly through its effects on body composition in adults with metabolic syndrome.

The role of the fat body in supporting ovarian growth was studied in the lizard Anolis carolinensis. Environmental and social stimulation of ovarian growth in well‐fed animals was not accompanied by reductions in fat body weight or by increases in serum nonesterified fatty acid (NEFA) levels. Adiposectomy had no effect on serum NEFA, but did reduce hepatic glycogen compared to sham‐operated controls. Adiposectomized lizards receiving injections (either hormone or carrier) also had lower hepatic glycogen levels when compared to uninjected controls. Administration of estradiol to ovariectomized lizards was effective in increasing serum levels of NEFAs, but had little effect on fat body weights. Follicle‐stimulating hormone (FSH) administration increased serum free fatty acid levels in sham‐operated lizards but was without effect in adiposectomized animals. It is concluded that the lipids contained in the lizard fat body are not preferentially utilized for reproduction and may not be used for that purpose if adequate energy is supplied from other sources.

Objective To investigate the relationship between serum adiponectin level and liver fat content as well as other related clinical parameters in patients with type 2 diabetes. Methods A total of 108 patients newly diagnosed with type 2 diabetes in the Third Central Hospital of Tianjin were selected. According to the liver fat content, subjects were divided into type 2 diabetic patients with low liver fat content group (T2DM+ LFC group, n=50) and type 2 diabetic patients with high liver fat content group (T2DM+ HFC group, n=58). The related clinical indexes and serum adiponectin level were measured by high performance liquid chromatography, glucose oxidase method, radioimmunoassay or ELISA. Comparison between groups were using t test or χ2 test. Spearman correlation analysis and multiple stepwise regression analysis were used to determine the relationship between indexes. Logistic regression analysis was used to analyze the risk factors of liver fat content. Results The level of serum adiponectin in T2DM+ HFC group was significantly lower than that in T2DM+ LFC group (t=3.947, P=0.006). The level of serum adiponectin was negatively correlated with body weight, body mass index, body fat, visceral fat area, liver fat content, and triglyceride in type 2 diabetic patients(r=-0.680--0.225, P<0.05 or 0.01). Stepwise regression indicated that body weight, body mass index and body fat content were independent correlated factors of serum adiponectin level. Logistic regression analysis showed that body weight (OR=1.288, 95% CI: 1.009-1.644), adiponectin(OR=0.169, 95% CI: 0.053-0.542), γ-glutamine transpeptidase (OR=1.155, 95% CI: 1.032-1.293) and triyglyceride (OR= 0.323, 95% CI: 0.172-0.609) were risk factors for liver fat content in patients with type 2 diabetes. Conclusion Level of serum adiponectin is affected by body weight, body mass index and body fat content, and may play an important role in lipid deposition in the liver of type 2 diabetic patients. Key words: Type 2 diabetes mellitus; Adiponectin; Insulin resistance; Fatty liver disease

The rs738409 C>G variant of the patatin-like phospholipase domain containing 3 gene (PNPLA3) increases the risk of non-alcoholic fatty liver disease (NAFLD) with no predisposition for insulin resistance. In this study, we aimed to investigate the influence of PNPLA3 polymorphisms on liver fat content (LFC) and glucose metabolic variables, and the associations between these, during the natural course of body weight changes in a Chinese adult cohort. The LFC, measured using a quantitative ultrasound method, was prospectively monitored in 2189 middle-aged and elderly adults from the Shanghai Changfeng Study, together with changes in body weight and metabolic variables. General linear models were used to detect interactive effects between the PNPLA3 rs738409 genotype and 4year changes in body weight on liver steatosis and glucose metabolism. The PNPLA3 homozygous GG genotype dissociated the changes in the LFC and OGTT 2h post-load blood glucose (PBG) in relation to 4year changes in body weight. PNPLA3 GG genotype carriers showed greater increases in the LFC and serum alanine aminotransferase (ALT) but lower PBG elevation and incident diabetes than PNPLA3 wild-type (CC) genotype carriers exhibiting the same degree of body weight increase. The interactions between the PNPLA3 genotype and changes in body weight on the LFC (false discovery rate [FDR]-adjusted pinteraction = 0.044) and ALT (FDR-adjusted pinteraction = 0.044) were significant. Subgroup analyses showed that the effect of the PNPLA3 GG genotype on changes in the LFC and PBG was only observed in metabolically unhealthy participants with insulin resistance or abdominal obesity. The PNPLA3 GG genotype interacted with changes in body weight to aggravate liver steatosis but reduced the risk of incident type 2 diabetes in metabolically unhealthy participants.

Effects of Different Cereal Grains in Diets for Laying Hens on Production Parameters and Liver Fat Content ,

1. Two long-term experiments were conducted with Single Comb White Leghorn (SCWL) hens (line UCD-003) predisposed to fatty liver haemorrhagic syndrome (FLHS). The first investigated the effect of adding a fatty liver supplement to the diet of laying hens prior to the onset of lay, and continuing either until peak production or throughout 39 weeks into lay. The second experiment, lasting 9 months into lay, investigated the effect of adding a fatty liver supplement, with or without 100 g/kg dietary ground flaxseed, to the diet. Body weight, feed intake, plasma triglycerides (in experiment 2) and egg production were measured throughout the experiment. Liver weight, liver fat content, liver malondialdehyde (MDA) content and liver haemorrhage score and fatty acid content of liver fat (in experiment 2) were measured at the end of each experiment. 2. In experiment 1, hens given diets containing the fatty liver supplement had higher egg production and eggshell strength, but there was no difference in liver parameters including MDA content or haemorrhage score compared with controls. 3. At the end of experiment 2, hens on 100 g/kg flaxseed diets had lower body weight, liver weight, liver dry matter and fat content, and plasma triglyceride concentrations than hens given the control diets. 4. Liver haemorrhage score was positively correlated with liver weight, but not with liver fat content, plasma triglyceride concentration or liver MDA content. This suggests that reducing the liver lipid content or feeding fatty liver supplements may not be as effective in controlling FLHS as controlling the size of the liver.