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ENDO 2021

A Little Help From My Friends: The Endocrinology-Psychiatry Interface - How Do We Help Each Other?

technical paper

Evaluation of Female Fertility: Antimullerian Hormone and Ovarian Reserve Testing

Endothelin-1 (ET-1) is elevated in patients with obesity; however, its contribution to the pathophysiology related to obesity is not fully understood. Obesity is associated with dyslipidemia and insulin resistance, which may in part be mediated by inflammation and alterations to immune cell subsets within the adipose tissue. ET-1 promotes inflammation via the ET-1 type A (ETA) receptor, and blockade of ETA receptors improves dyslipidemia in patients with chronic kidney disease. We hypothesized that ET-1 causes dyslipidemia and inflammation within the adipose tissue of obese mice. To test this hypothesis, C57BL/6J mice were fed either normal diet (NMD) or high fat diet (HFD) for 8 weeks followed by 2 weeks of treatment with either vehicle or atrasentan (ETA receptor antagonist, 10mg/kg/day). HFD mice had significantly higher fat mass than NMD mice, with no significant effect of treatment with atrasentan. HFD mice had significantly higher circulating non-esterified free fatty acids, an effect that was ameliorated in mice treated with atrasentran (1.03±0.07 vs 0.58±0.02 mEq/L, p<0.05). Atrasentan-treated mice had significantly attenuated increase in liver triglycerides compared to non-treated HFD mice (3.8±0.7 vs 7.5±1.3mg/dL respectively, p<0.05). Mice treated with atrasentan had significantly improved glucose tolerance (10150±1031 vs 6563±975 AUC, p<0.05) and insulin tolerance (-2796±386 vs -9825±319 AUC, p<0.05) compared to non-treated insulin-resistant HFD mice. Plasma adiponectin, an insulin sensitizing adipokine that is inversely associated with adiposity and insulin resistance, was significantly increased in atrasentan-treated mice compared to non-treated HFD (4.8±0.1326 vs 6.5±0.3 µg/ml, p<0.05), with no differences in plasma insulin levels. Gene expression analysis of visceral fat showed improved expression of genes negatively associated with insulin resistance that were downregulated in non-treated HFD mice vs. NMD (IRS-1, PPAR-gamma, GLUT4, and adiponectin). Flow cytometric analyses of visceral adipose tissue indicated that HFD mice had a significantly higher number of both CD4+ and CD8+ T cells compared to NMD mice, which was attenuated by treatment with atrasentan. Further, eosinophils, which are important in maintaining adipose tissue health and reducing inflammation, were significantly decreased in HFD mice compared to NMD. Atrasentan treatment abolished the decrease in eosinophils. Taken together, these data indicate that ETA receptor blockade improves peripheral glucose homeostasis, dyslipidemia, and liver triglyceride levels, and also attenuates the proinflammatory immune profile in visceral adipose tissue. These data suggest a potential use for ETA receptor blockers in the treatment of obesity-associated dyslipidemia and insulin resistance.?? 

Endothelin-1 Receptor A Blockade Attenuates Metabolic and Proinflammatory Profile in Mice Fed a High Fat Diet

Activin A Plays a Key Role in Cancer Cachexia Progression

Introduction: Obesity is characterized by mobilization of macrophage inflammation, which represents the major events of obesity-associated adipose tissue inflammation. . On the other hand, lactate accumulation in adipose tissue long been observed.However, whether elevation of lactate plays an essential role in adipose inflammation is not known. In this study, we sought to examine the intermediary role of lactate in macrophage polarization and adipose inflammation upon obesity.Method: Lactate level and activity of lactate dehydrogense (LDH), the key enzyme of lactate production, were measured by biochemical assays. Adipocyte- and macrophage- specific Ldha knock out mice were constructed by cre-LoxP system to study the physiological role of lactate in diet induced obesity. Macrophage polarization and inflammation were examined by western blotting and Q-PCR.Results: Lactate and LDH activity were selectively upregulated in adipose tissues of obese mice. Adipocyte-, but not macrophage-selective deletion of LDHA, led to a significant improvement of adipose inflammation and metabolic dysfunctions. In vitro experiments showed that the lactate promoted M1 polarization through direct interation and inhibition of the PHD2, which subsequently stabilizes HIF-1alpha. In addition, a positive correlation between adipose lactate level and adipose tissue inflammation was found in obese patients. Conclusion: In obese condition, increased production of lactate from adipocytes enhances adipose tissue inflammation by promoting the proinflammatory polarization of adipose macrophages.?? 

Adipocyte-Derived Lactate Potentiates Obesity-Evoked Adipose Macrophage Inflammation

Breast Cancer Endocrine Therapy Exhausts Adipocyte Progenitors Promoting Weight Gain and Glucose Intolerance

The Solution for a Yet Unsolvable Problem?
Dextroamphetamine Treatment for Acquired or Genetic Hypothalmic Obesity

Weight Loss, Improved Body Composition and Fat Distribution by Tesomet in Acquired Hypothalamic Obesity
- An RCT of Tesomet in Acquired Hypothalmic Obesity

Background: In people with overweight or obesity, long-term maintenance of weight loss is challenging. Subcutaneous (s.c.) semaglutide, a glucagon-like peptide-1 analogue, has shown clinically-relevant weight loss in a phase 2 trial in people with obesity. STEP 4 investigated the impact of continued semaglutide 2.4 mg treatment, vs switching to placebo, on maintenance of weight loss in participants who reached 2.4 mg of semaglutide during a run-in period.?Methods: This was a 68-week withdrawal trial (NCT03548987) in 902 subjects aged ≥18 years with body mass index (BMI) ≥30 kg/m2 (or BMI ≥27 kg/m2 with ≥1 weight-related comorbidity), without diabetes. Following a 20 week run-in period, 803 subjects who reached the maintenance dose of once-weekly (OW) s.c. semaglutide 2.4 mg were randomized 2:1 to continue treatment with semaglutide 2.4 mg or switch to placebo for 48 weeks, both as adjunct to lifestyle intervention. The primary endpoint was percentage change in body weight between randomization (week 20) and week 68. Confirmatory secondary endpoints included change in waist circumference and systolic blood pressure. Two estimands were defined: treatment policy and trial product; results are presented for the treatment policy estimand, unless stated otherwise.?Results: Mean body weight (±SD) was 107.2 ±22.7 kg at week 0 and 96.1 ±22.6 kg at randomization (week 20; mean change -10.6%). Randomized participants were mostly female (79%) and white (84%); mean age was 46 years and mean BMI was 34.4 kg/m2. Between weeks 20-68, estimated mean body weight change was −7.9% vs +6.9% for semaglutide 2.4 mg vs placebo (estimated treatment difference [ETD]: −14.8%; 95% confidence interval [CI]: −16.0, −13.5; p<0.0001), and -8.8% vs 6.5%, respectively, for the trial product estimand (ETD: -15.3%; 95% CI: -16.5, -14.1; p<0.0001). For participants randomized to continue semaglutide, the estimated change in body weight from week 0-68 was -17.4% (-18.2% for trial product estimand). Continued semaglutide treatment (weeks 20-68) led to clinically-relevant improvements in waist circumference, systolic blood pressure, BMI, HbA1c, FPG, and lipids (total cholesterol, LDL, VLDL, and triglycerides) vs switching to placebo (p<0.0001 for all). During the run-in period, 5.3% of participants discontinued treatment due to adverse events; during the randomized period, 2.4% (semaglutide) and 2.2% (placebo) discontinued. Nausea, diarrhea and constipation (mostly transient and mild-to-moderate) were the most frequent adverse events with semaglutide.?Conclusion: In adults with overweight or obesity, continued treatment after dose escalation with OW s.c. semaglutide 2.4 mg until week 68 led to clinically-relevant weight loss, while switching to placebo led to significant weight regain; these data underscore the chronicity and relapsing nature of obesity, and the need for continued treatment.?? 

Weight Loss Maintenance With Once-Weekly Semaglutide 2.4 MG in Adults With Overweight or Obesity Reaching Maintenance Dose (STEP 4)

Background: In adolescents with severe obesity, long-term weight loss maintenance using lifestyle therapy alone is hampered by numerous biological adaptations favoring weight regain such as increased appetite and sense of food palatability and decreased satiety and resting energy expenditure. Anti-obesity pharmacotherapy may have a role in mitigating some of these physiological adaptations, thereby enhancing weight loss maintenance. We conducted a randomized, double-blind, placebo-controlled clinical trial to evaluate the effect of the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide extended release (XR) on the maintenance of BMI reduction and improvements in cardiometabolic risk factors induced by short-term meal replacement therapy (MRT) among adolescents with severe obesity. Methods: One-hundred adolescents ages 12 to <18 years with BMI ≥120% of the 95th percentile engaged in an MRT intervention consisting of pre-portioned meals averaging 1,400 kcals/day with a goal of reducing BMI by ≥5% within eight weeks. Participants achieving this goal were randomized 1:1 to either exenatide XR (2 mg/week subcutaneously) + lifestyle therapy or matching placebo + lifestyle therapy for a subsequent 52 weeks. The primary outcome was mean percent change in BMI from randomization (post-MRT) to 52 weeks. Secondary outcomes included changes in body fat (DXA) and cardiometabolic risk factors. Results: Sixty-six participants (mean age 16±1.5 years; 47% female; mean BMI 36.9±4.4 kg/m2) achieved ≥5% BMI reduction with MRT and were randomized; 56 (85%) completed the 52-week visit. From randomization (post-MRT) to 52-weeks, the exenatide and placebo group mean BMI increased 4.6% and 10.1%, respectively. The prespecified intention-to-treat, last observation carried forward primary analysis demonstrated a placebo-subtracted exenatide treatment effect of -4.1% (95% CI -8.6 to 0.5, p=0.078). The per-protocol analysis (excluding participants with major protocol deviations) demonstrated a placebo-subtracted exenatide treatment effect of -5.7% (95% CI -10.9 to -0.6, p=0.030). The placebo-subtracted exenatide treatment effect on total body fat was -3.0 kg (95% CI -6.7 to 0.7, p=0.108), systolic blood pressure -3.2 mmHg (95% CI -7.0 to 0.7, p=0.107), and triglycerides to HDL ratio -0.6 (95% CI -1.2 to 0.0, p=0.050). Exenatide was generally well-tolerated and the adverse event profile was similar to previous reports of GLP-1RAs. Conclusion: The steep trajectory of weight regain following short-term MRT, particularly in the placebo group, underscores the challenge many adolescents encounter in maintaining weight loss over time. GLP-1RA treatment with once-weekly exenatide appears to partly mitigate the propensity toward weight regain after initial dietary-induced weight loss among adolescents with severe obesity.?? 

Once-Weekly Exenatide Enhances Weight Loss Maintenance in Adolescents with Severe Obesity: A Randomized, Placebo-Controlled Trial

CRN04894 is an orally administered nonpeptide that is a potent and selective antagonist for adrenocorticotropic hormone (ACTH) acting at the melanocortin 2 receptor (MC2R) and is currently under development for the treatment of diseases of ACTH excess such as Cushing’s disease, congenital adrenal hyperplasia, and ectopic ACTH-secreting tumors. Cushing’s disease results from an adenoma derived from pituitary corticotropic cells that secrete excess ACTH, whereas ectopic ACTH syndrome arises from nonpituitary ACTH secreting tumors. Congenital adrenal hyperplasia is a genetic disease that results in cortisol deficiency leading to high levels of ACTH and adrenal androgens. Each of these indications is characterized by high ACTH levels that act on MC2R expressed in the adrenal cortex to drive pathological elevations of adrenally derived steroid hormones. CRN04894 blocks the action of ACTH at MC2R, providing a potential novel treatment for these diseases. Preclinical models of chronic hypercortisolemia include implantation of ACTH-secreting pituitary tumor cells in mice and continuous administration of ACTH via subcutaneously implanted osmotic pumps in rats. These models induce features consistent with human diseases of ACTH excess including hypercortisolemia and hypertrophy of the adrenal glands. We employed both rodent models to examine the pharmacodynamic effects of CRN04894 on corticosterone levels and adrenal gland morphology. In the mouse pituitary tumor model, subcutaneous inoculation of the ACTH-secreting mouse pituitary tumor cell line, AtT-20, into immunodeficient mice resulted in formation of tumors and increased plasma ACTH and corticosterone levels. Repeated daily oral administration of CRN04894 for 14 days dose-dependently and robustly suppressed plasma corticosterone levels in mice with AtT-20 tumors. In the rat model, subcutaneous implantation of osmotic pumps delivering ACTH resulted in increased corticosterone levels, reduction in body weight, and hypertrophy of the adrenal glands after 7 days. Daily oral administration of CRN04894 over 7 days dose-dependently suppressed corticosterone levels, mitigated the effect of ACTH excess on body weight, and rescued the adrenal gland hypertrophy. These findings provide evidence that CRN04894 functions as an effective ACTH antagonist at MC2R to suppress adrenal corticosterone secretion in both mouse and rat models of ACTH excess and hypercortisolemia, thus providing a strong rationale for its potential therapeutic utility in diseases of ACTH excess. This work was supported in part by an SBIR grant from the NIH awarded to Dr. Struthers (R43- DK115245)?? 

A Little Help From My Friends: The Endocrinology-Psychiatry Interface - How Do We Help Each Other?

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