Objectives Beta‐3 adrenergic receptors (β3‐AR) stimulate lipolysis and thermogenesis in white and brown adipose tissue (WAT and BAT). Obesity increases oxidative stress and inflammation that attenuate AT β3‐AR signaling. The objective of this study was to test the hypothesis that the combination of the β3‐AR agonist CL‐316,243 (CL) and the antioxidant alpha‐lipoic acid (ALA) would lower inflammation in diet‐induced obesity (DIO) and improve β3‐AR function. Methods A total of 40 DIO mice were separated into four groups: Control (per os and intraperitoneal [IP] vehicle); CL alone (0.01 mg/kg IP daily); ALA alone (250 mg/kg in drinking water); or ALA+CL combination, all for 5 weeks. Results Food intake was similar in all groups; however, mice receiving ALA+CL showed improved body composition and inflammation as well as lower body weight (+1.7 g Control vs. −2.5 g ALA+CL [−7%]; p < 0.01) and percentage of body fat (−9%, p < 0.001). Systemic and epididymal WAT inflammation was lower with ALA+CL than all other groups, with enhanced recruitment of epididymal WAT anti‐inflammatory CD206+ M2 macrophages. β3‐AR signaling in WAT was enhanced in the combination‐treatment group, with higher mRNA and protein levels of thermogenic uncoupling protein 1 and AT lipases. Conclusions Chronic treatment with ALA and a β3‐AR agonist reduces DIO‐induced inflammation. AT immune modulation could be a therapeutic target in patients with obesity.
Bile acids (BAs) are classically known as facilitators of fat digestion. Moreover, they are now known to be ligands for receptors involved in glucose and lipoprotein metabolism. BA synthesis was originally thought to be exclusive to hepatic tissue, but emerging evidence in rodents has demonstrated the expression of BA transporters and de novo synthetic enzymes in murine adipose tissue. We previously showed that chronic activation of brown adipose tissue (BAT) and white adipose tissue (WAT) in adult women via the β3-adrenergic receptor (ADRB3) agonist mirabegron increases total plasma BA levels. The largest increases were seen with primary unconjugated BAs. Overall, these data suggest that chronic adrenergic stimulation may increase the synthesis and activity of BA synthesis enzymes in human adipose tissue, which contributes to the increase in total plasma BAs. To confirm this hypothesis, we measured expression levels of BAT and BA synthesis enzymes in liver and adipose tissues collected from healthy patients and those with pheochromocytoma (pheo) who experienced chronic adrenergic activation. As expected, expression of thermogenic UCP1 and ADRB3 was higher in pheo peri-renal BAT than in liver tissue (76,000x, P<0.001; and 6,000x, P=0.02, respectively) or either healthy subcutaneous WAT or pheo subcutaneous WAT (≥1500x, P<0.001 for UCP1). Conversely, expression of the rate-determining enzyme in BA synthesis CYP7A1 was similar in liver and both WAT depots (P>0.05), and liver had slightly higher expression than BAT (3x, P=0.03). Otherwise, most of the principal BA synthesis genes’ expression levels demonstrated the following stepwise pattern: liver tissue > pheo WAT = subcutaneous WAT > BAT (CYP8B1, CYP27A1, AKR1D1, and BAAT). These results suggest that BA production in humans is not limited to the liver. Rather, human WAT in particular may contribute to the BA pool and could serve as a target for producing BA-mediated improvements in glucose and lipoprotein metabolism. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
Cushing Syndrome (CS) is characterized by cortisol excess that leads to impaired glucose tolerance and obesity. CT imaging shows 20% of CS patients have nonalcoholic steatohepatitis (NASH). While the gold standard diagnostic test for NASH is liver biopsy, it has too much risk for CS patients. This study evaluated the ability of noninvasive, magnetic resonance spectroscopy (MRS) to measure liver fat percentage in CS patients and followed temporal changes in metabolic parameters before and after successful treatment. The primary outcome was protein density fat fraction (PDFF) by MRS at 3 timepoints: baseline, 6 months, and 12 months after treatment, which consisted of surgery as indicated based on ACTH source. The diagnosis was confirmed if there was histology consistent with corticotrope adenoma, adrenal tumor, or an ectopic source. We prospectively studied 41 consecutive patients: 85% female; 44±1.8 y; 32.6±1.5 kg/m²; urine cortisol excretion 2242.7±1806.3 [nl 3.5-45.0 mcg/24h]). Each underwent MRS at 3T where NASH was defined as >5% PDFF. A1c and BMI were measured. Changes over time were evaluated using Wilcoxon signed-rank test, and correlation among variables was done with Spearman’s rank test. At baseline, mean PDFF was 10.4±1.7 and correlated positively with BMI (r=0.57, P<0.001). NASH was present in 32% of patients. PDFF reductions were similar after 6 and 12 months of treatment (-52%, P=0.001 and -50%, P=0.02); rates of NASH declined to 13% and 11%; BMI decreased (-9%; P=0.002 and -12%, P<0.001). A1c was lower at 12 months (6.2±1.1 to 5.6±0.5, P<0.001). The reduction in liver fat correlated with changes in visceral fat mass (r=0.70, P<0.001). In summary, MRS-PDFF was effective at diagnosing NASH in CS. Physiologically, definitive treatment of CS reduced liver fat by 6 months after normalization of cortisol and also preceded the improvement in A1c. These results suggest that liver insulin resistance due to fat accumulation has an important role in diabetes pathophysiology in CS. Disclosure A. Pierce: None. Z. A. Sater: None. A. M. Cypess: None.
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