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Aims/hypothesisIn vitro and rodent studies suggest that pioglitazone, a thiazolidinedione, can promote adipogenesis in adipose tissue (AT); however, there is a lack of in vivo studies in humans to support these findings. The objectives of this randomised, placebo-controlled, parallel-arm trial were to test if pioglitazone stimulates in vivo adipogenesis in the subcutaneous adipose tissue depots and if these measures were related to metabolic health outcomes in women with obesity.MethodsForty-one healthy women with obesity (20 black; 21 white; 29 ± 6 years; BMI 32.0 ± 1.7 kg/m2; 44.0 ± 3.6% body fat) were randomised to consume 30 mg/day of pioglitazone (n = 21) or placebo (n = 20) for 16 weeks. SAS v9.4 was used to generate the block randomisation code sequence (stored in password-protected files) with a 1:1 allocation ratio. The participants and study staff involved in assessing and analysing data outcomes were blinded to the group assignments. The trial was conducted at Pennington Biomedical Research Center and ended in 2016. At baseline and post-intervention, subcutaneous abdominal (scABD) and femoral (scFEM) AT biopsies were collected, and in vivo cellular kinetics (primary endpoint of the trial) were assessed by an 8 week labelling protocol of deuterium (2H) into the DNA of adipose cells. Body composition was measured by dual-energy x-ray absorptiometry (DXA), scABD and visceral AT (VAT) by MRI, ectopic fat by 1H-MRS, and insulin sensitivity by an OGTT.ResultsAfter the 16 week intervention, there was a significant decrease in visceral fat (VAT:total abdominal AT [as a %]; p = 0.002) and an increase in the Matsuda index (i.e. improved insulin sensitivity; p = 0.04) in the pioglitazone group relative to the placebo group. A significant increase in the formation of new adipocytes was observed in the scFEM (Δ = 3.3 ± 1.6%; p = 0.04) but not the scABD depot (Δ = 2.0 ± 2.1%; p = 0.32) in the pioglitazone group relative to the placebo group. No serious adverse events were reported.Conclusions/interpretationPioglitazone may elicit distinct differences in in vivo adipogenesis in subcutaneous adipose depots in women with obesity, with increased rates in the protective scFEM.Trial registrationClinicalTrials.govNCT01748994Funding This study was funded by R01DK090607, P30DK072476, and R03DK112006 from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health. The Robert C. and Veronica Atkins Foundation.

d-allulose is a rare sugar with zero energy that can be consumed by obese/overweight individuals. Many studies have suggested that zero-calorie d-allulose has beneficial effects on obesity-related metabolism in mouse models, but only a few studies have been performed on human subjects. Therefore, we performed a preliminary study with 121 Korean subjects (aged 20–40 years, body mass index ≥ 23 kg/m2). A randomized controlled trial involving placebo control (sucralose, 0.012 g × 2 times/day), low d-allulose (d-allulose, 4 g × 2 times/day), and high d-allulose (d-allulose, 7 g × 2 times/day) groups was designed. Parameters for body composition, nutrient intake, computed tomography (CT) scan, and plasma lipid profiles were assessed. Body fat percentage and body fat mass were significantly decreased following d-allulose supplementation. The high d-allulose group revealed a significant decrease in not only body mass index (BMI), but also total abdominal and subcutaneous fat areas measured by CT scans compared to the placebo group. There were no significant differences in nutrient intake, plasma lipid profiles, markers of liver and kidney function, and major inflammation markers among groups. These results provide useful information on the dose-dependent effect of d-allulose for overweight/obese adult humans. Based on these results, the efficacy of d-allulose for body fat reduction needs to be validated using dual energy X-ray absorption.

Aims Soluble dipeptidyl peptidase‐4 (sDPP‐4) is secreted by hepatocytes and induces adipose tissue inflammation and insulin resistance. Sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors can improve hepatic steatosis by inhibiting hepatic de novo lipogenesis. We investigated the effects of dapagliflozin (an SGLT2 inhibitor) on serum levels of sDPP‐4 in patients with type 2 diabetes and non‐alcoholic fatty liver disease (NAFLD). Methods Fifty‐seven patients with type 2 diabetes and NAFLD were randomized to a dapagliflozin group (5 mg/d for 24 weeks) (n = 33) or the control group (n = 24). Serum levels of sDPP‐4 were measured with a commercial ELISA kit. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were measured by dual bioelectrical impedance analysis. Results In a total of 57 patients, baseline serum sDPP‐4 was positively correlated with aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ‐glutamyl transferase (GGT) and HOMA‐IR Both VAT and SAT areas decreased significantly in the dapagliflozin group alone. Liver enzymes were decreased at 24 weeks in the dapagliflozin group, but were unchanged in the control group. Although both groups showed significant reduction of serum sDPP‐4 after 24 weeks of treatment, the magnitude of decrease was significantly larger in the dapagliflozin group. Changes in liver enzymes during treatment with dapagliflozin were positively correlated with the change in serum sDPP‐4, but not with changes in VAT volume or HbA1c. Conclusions Improvement of liver dysfunction after treatment with dapagliflozin was associated with a decrease in serum sDPP‐4, suggesting that reduction of serum sDPP‐4 by SGLT2 inhibitors may be a therapeutic strategy for NAFLD/NASH in patients with type 2 diabetes that is independent of glucose lowering or weight loss.

ContextAlthough the long-term effects of testosterone on adipose tissue lipid metabolism in men have been defined, the short-term regulation of these effects is not well understood.ObjectiveWe examined the effects of acute testosterone withdrawal on subcutaneous abdominal and femoral adipose tissue fatty acid (FA) storage and cellular mechanisms.DesignThis was a prospective, randomized trial.SettingMayo Clinic Clinical Research Unit.Patients or ParticipantsThirty-two male volunteers ages 18 to 50 participated in these studies.InterventionsVolunteers were randomized to receive (1) no treatment (control), (2) injections (7.5 mg) of Lupron®, or (3) Lupron and testosterone (L+T) replacement for 49 days, resulting in 4 weeks of sex steroid suppression in the Lupron group.Main Outcome MeasuresWe measured body composition, fat cell size, adipose tissue meal FA and direct free FA storage, lipoprotein lipase (LPL), acyl coenzyme A synthetase (ACS), diacylglycerol acyltransferase activities, and CD36 content.ResultsCompared with control and L+T groups, acute testosterone deficiency resulted in greater femoral adipose tissue meal FA storage rates, fasting and fed LPL activity, and ACS activity.ConclusionsThese results suggest that in men, testosterone plays a tonic role in restraining FA storage in femoral adipose tissue via suppression of LPL and ACS activities. FA storage mechanisms in men appear sensitive to short-term changes in testosterone concentrations.Acute testosterone deficiency in men results in greater femoral adipose lipoprotein lipase and acyl coenzyme A synthetase activities, which correlates with greater meal fat and direct FFA storage.

•This randomized, double-blind trial compared 2 AYP-101 concentrations (25 mg/mL and 50 mg/mL) with placebo for submental fat reduction.•The 25 mg/mL group significantly improve subjective outcomes compared to placebo, while no significant differences were observed in objective volume reduction.•Both concentrations were well-tolerated, although the 25 mg/mL group exhibited fewer adverse effects. Submental fat (SMF) accumulation can affect self-image and psychological well-being, leading to a demand for nonsurgical treatment. AYP-101, which contains soybean phosphatidylcholine (SPC), is under investigation for SMF reduction. This study aimed to compare 2 concentrations of AYP-101 to placebo injections to determine the optimal concentration and evaluate safety and efficacy in reducing moderate to severe SMF in an Asian population. This single-center, randomized, double-blind, placebo-controlled phase II trial enrolled 96 participants with moderate to severe SMF. Participants were randomly assigned to receive either a placebo or AYP-101 at either a low concentration (25 mg/mL) or a high concentration (50 mg/mL), administered every 2 weeks for up to 6 sessions. The primary endpoint was the proportion of participants achieving at least a 1-grade improvement in both the Evaluator-Reported Submental Fat Rating Scale (ER-SMFRS) and the Subject-Reported Submental Fat Rating Scale (SR-SMFRS) at 4 and 12 weeks after the final injection. At 4 weeks post-treatment, 69.70% of the low-concentration group and 48.39% of the high-concentration group exhibited improvement in the ER-SMFRS, compared to 22.58% in the placebo group. Significant differences were noted between the low-concentration and placebo groups (P = 0.0002), with similar results at 12 weeks. AYP-101, administered biweekly at a concentration of 25 mg/mL, appears to be a safe and effective nonsurgical option for reducing SMF in Asians.

Introduction The study investigates the efficacy of combining low‐dose triamcinolone acetonide (TAC) and lidocaine with deoxycholic acid (DCA) injections to reduce adverse effects (AEs) without compromising long‐term results. Methods A double‐blind, randomized trial was conducted with 15 subjects, divided into a control group (DCA with lidocaine) and an intervention group (DCA with low‐dose TAC and lidocaine). The primary outcomes measured were injection pain, swelling, and submental fat reduction. Results Results indicated that the intervention group experienced significantly reduced pain and swelling compared to the control group. Both groups showed similar efficacy in submental fat reduction, with the intervention group demonstrating a greater mean volumetric loss. Conclusion The study concludes that the addition of low‐dose TAC and lidocaine to DCA injections is a safe and effective method to enhance patient comfort and treatment outcomes without inducing steroid‐related side effects.

PurposeObesity is characterized by insulin resistance and low-grade systemic and adipose tissue (AT) inflammation. It remains unclear whether beneficial effects of weight loss are related to AT inflammation. We aimed to assess the effect of weight loss during low-calorie diet on insulin sensitivity, AT expression of genes associated with inflammation in young subjects with obesity. Furthermore, we estimated the effects of immunomodulatory (1, 3)(1, 6)-β-glucan (BG) on the above parameters.MethodsThe study group comprised 52 subjects with obesity. Twelve-week dietary intervention was applied, with randomization to receive or not 500 mg BG daily. Euglycemic hyperinsulinemic clamp, subcutaneous AT biopsy were performed before and after the program. Twenty normal-weight subjects, examined at baseline, served as a control group.ResultsAt baseline, obese subjects had lower insulin sensitivity, lower AT ADIPOQ, JAK1, and JAK2 expression and higher AT expression of LEP, IL6ST, STAT3, MIF, CCL2, MMP9, and IL18. Forty obese subjects completed dietary intervention program, which resulted in 11.3% weight loss and 27% increase in insulin sensitivity (both p < 0.0001). AT IL6R, IL6ST, JAK1, and JAK2 expression increased, whereas MIF, CCL2, MMP9, and IL18 gene expression did not change in response to weight loss. BG addition had no effect on any of the parameters studied.ConclusionsOur data indicate that reduction in AT inflammation is not required for an improvement in insulin action during weight loss in subjects with uncomplicated obesity. BG does not have effects during dietary intervention.

Abstract Aims Hypoglycemia hinders optimal glycemic management in type 1 diabetes (T1D). Long diabetes duration and hypoglycemia impair hormonal counter-regulatory responses to hypoglycemia. Our study was designed to test whether (1) the metabolic responses and insulin sensitivity are impaired, and (2) whether they are affected by short-lived antecedent hypoglycemia in participants with T1D. Materials and Methods In a randomized, crossover, 2x2 factorial design, 9 male participants with T1D and 9 comparable control participants underwent 30 minutes of hypoglycemia (p-glucose < 2.9 mmol/L) followed by a euglycemic clamp on 2 separate interventions: with and without 30 minutes of hypoglycemia the day before the study day. Results During both interventions insulin sensitivity was consistently lower, while counter-regulatory hormones were reduced, with 75% lower glucagon and 50% lower epinephrine during hypoglycemia in participants with T1D, who also displayed 40% lower lactate and 5- to 10-fold increased ketone body concentrations following hypoglycemia, whereas palmitate and glucose turnover, forearm glucose uptake, and substrate oxidation did not differ between the groups. In participants with T1D, adipose tissue phosphatase and tensin homolog (PTEN) content, hormone-sensitive lipase (HSL) phosphorylation, and muscle glucose transporter type 4 (GLUT4) content were decreased compared with controls. And antecedent hypoglycemic episodes lasting 30 minutes did not affect counter-regulation or insulin sensitivity. Conclusions Participants with T1D displayed insulin resistance and impaired hormonal counter-regulation during hypoglycemia, whereas glucose and fatty acid fluxes were intact and ketogenic responses were amplified. We observed subtle alterations of intracellular signaling and no effect of short-lived antecedent hypoglycemia on subsequent counter-regulation. This plausibly reflects the presence of insulin resistance and implies that T1D is a condition with defective hormonal but preserved metabolic responsiveness to short-lived hypoglycemia.

Background We have previously shown that a combination of glucosyl hesperidin (G-hesperidin) plus caffeine reduces accumulation of body fat, whereas G-hesperidin or caffeine alone shows little effect on high-fat diet-induced obesity in mice. The aim of this study is to evaluate the anti-obesity effect of G-hesperidin plus caffeine on body fat and serum TG in healthy subjects with moderately high body mass index (BMI) and serum TG. Since we considered that there are individual differences in caffeine sensitivity, we conducted dose-finding study of caffeine combined with G-hesperidin. Methods Seventy-five healthy subjects with moderately high BMI (24–30 kg/m 2 ) and serum TG (100–250 mg/dl) were divided and assigned to 12-week intervention with daily intakes of 500 mg of G-hesperidin with or without 25, 50, or 75 mg of caffeine, or placebo in a randomized double-blind placebo-controlled design . Results After intervention, decreases in abdominal fat area (AFA), especially subcutaneous fat area (SFA), were significantly greater in the G-hesperidin with 50-mg caffeine group (AFA:-8.4 ± 21.9 v.s. 16.3 ± 34.1 cm 2 ; p  < 0.05, SFA: -9.3 ± 17.1 v.s. 11.2 ± 18.3 cm 2 ; p  < 0.01) and in the G-hesperidin with 75-mg caffeine group (AFA:-17.0 ± 31.4 v.s. 16.3 ± 34.1 cm 2 ; p  < 0.01, SFA: -12.4 ± 18.7 v.s. 11.2 ± 18.3 cm 2 ; p  < 0.01) than in the placebo group. Fat-decreasing effects of G-hesperidin were enhanced dose-dependently by caffeine addition. BMI decreases were significantly greater in the G-hesperidin with 75-mg caffeine group than in the placebo group (-0.56 ± 0.74 v.s. -0.02 ± 0.58 kg/m 2 ; p  < 0.05). G-hesperidin with/without caffeine had no effect on serum TG ( p  > 0.05 v.s. placebo). Conclusions These data suggested that a combination of 500-mg G-hesperidin with 50- or 75-mg caffeine may be useful for the prevention or treatment of obesity. Trial registration UMIN Clinical Trials Registry 000019241 .

The prevalence of overweight/obesity is continuing its relentless global rise. In this condition, the risk of some disorders such as cardiovascular diseases, hypertension, diabetes mellitus, hirsutism, menstrual abnormalities, gallbladder disease, arthritis, and some site-specific cancers is increased. In the current study, we assessed the efficacy of carboxytherapy in reducing thickness of the abdominal subcutaneous fat through clinical and ultrasonographical studies. Our study was a prospective, randomized, single-blind, 2-split clinical trial in which 30 obese subjects with abdominal adiposity were recruited. In each case carboxytherapy was randomly done on the one side of abdomen (interventional group) every 2 weeks for 5 sessions, while the contralateral side was left without therapy (control group). Before every session, data of subjective and objective clinical assessments, body weight, BMI, waist circumference, and waist to hip circumference ratio were collected. Two weeks after the last session, the thickness of different skin layers was measured by ultrasonography in the both study groups. Of 30 subjects, 20 were female (66.67%) and 10 were male (33.33%), with mean age of 39.16 years (± 9.51). The mean weight, BMI, waist circumference, and waist to hip circumference ratio demonstrated significant decrease during the study. The subjective and objective assessments both showed significant improvement. The subcutis thickness revealed a statistically significant decrease in the interventional group, with no significant difference between males and females. No significant complication was reported. Carboxytherapy is a safe and effective modality in the management of local fat deposits.Clinical trial registry code: IRCT20220517054900N1.