Adiponectin is an adipocyte-derived adipokine with potent antidiabetic, anti-inflammatory, and antiatherogenic activity. Long-term, high-fat diet results in gain of body weight, adiposity, further inflammatory-based cardiovascular diseases, and reduced adiponectin secretion. Vitamin A derivatives/retinoids are involved in several of these processes, which mainly take place in white adipose tissue (WAT). In this study, we examined adiponectin expression as a function of dietary high-fat and high–vitamin A conditions in mice. A decrease of adiponectin expression in addition to an up-regulation of aldehyde dehydrogenase A1 (ALDH1A1), retinoid signaling, and retinoic acid response element signaling was selectively observed in WAT of mice fed a normal–vitamin A, high-fat diet. Reduced adiponectin expression in WAT was also observed in mice fed a high–vitamin A diet. Adipocyte cell culture revealed that endogenous and synthetic retinoic acid receptor (RAR)α- and RARγ-selective agonists, as well as a synthetic retinoid X receptor agonist, efficiently reduced adiponectin expression, whereas ALDH1A1 expression only increased with RAR agonists. We conclude that reduced adiponectin expression under high-fat dietary conditions is dependent on 1) increased ALDH1A1 expression in adipocytes, which does not increase all-trans-retinoic acid levels; 2) further RAR ligand–induced, WAT-selective, increased retinoic acid response element–mediated signaling; and 3) RAR ligand–dependent reduction of adiponectin expression.—Landrier, J.-F., Kasiri, E., Karkeni, E., Mihály, J., Béke, G., Weiss, K., Lucas, R., Aydemir, G., Salles, J., Walrand, S., de Lera, A. R., Rühl, R. Reduced adiponectin expression after high-fat diet is associated with selective up-regulation of ALDH1A1 and further retinoic acid receptor signaling in adipose tissue.
Introduction: Pembrolizumab is an immune checkpoint inhibitor (ICI) that blocks programmed cell death receptor 1 (PD-1) and is indicated in treatment of malignancies including lung adenocarcinoma and melanoma. Anti-PD-1 therapies are responsible for immune related adverse events including endocrine dysfunction. Here we present a case of Pembrolizumab induced hypophysitis causing central adrenal insufficiency apparently missed by a 250 mcg cosyntropin test. Clinical Case: A 68 year old female with history of COPD and stage 4 lung adenocarcinoma with bone metastases presented to the ED with hypotension during her 14th cycle of treatment with Pembrolizumab. Other symptoms included fatigue and anorexia for about 4 weeks. She denied vomiting, diarrhea, bleeding episodes or chronic steroid use. On exam, patient was obese and pale appearing, with decreased bilateral breath sounds without edema. Random cortisol on admission at 4:44 pm was 6.9 ug/dl, ACTH - was in process, Na was 135 (137 - 145 mEq/L) and K was 3.7 (3.5 - 5.1 mEq/L). A 250 mcg cosyntropin stimulation test resulted in 30 min cortisol level of 22.5 µg/dL and 60 min cortisol level of 34 µg/dL. Patient was treated with fluids, salt tabs and eventually midodrine, however BP remained borderline low. On day 5, the patient was started on IV methylprednisolone 40 mg Q8 hrs for COPD exacerbation. A few days later pre-steroid ACTH was reported as <5 pg/ml (6-50 pg/ml) which prompted further workup for hypopituitarism. LH and FSH levels were inappropriately low for a postmenopausal female at 0.2 and 2.6 mIU/ml respectively, Free T3 was 2.02 pg/ ml (2.77-5.27 pg/ml), free T4 was 1.07 ng/dl (0.80-2.20 ng/dl), and TSH was 0.67 uIU/ml (0.47-4.70 uIU/ml). MRI brain showed partially empty sella. Patient was diagnosed clinically with Pembrolizumab induced hypophysitis causing central adrenal insufficiency. Eventually, steroids were tapered to prednisone 5 mg daily maintenance dose and patient was discharged with stress dosing instructions. Conclusion: Diagnosis of adrenal insufficiency is challenging as advanced malignancy and adrenal insufficiency can cause similar symptoms. The finding of an empty sella here is a confounding factor. Checkpoint inhibitors are known to cause hypophysitis, thyroiditis and primary adrenal insufficiency, however incidence is <1%. We report a case of missed adrenal insufficiency by a falsely assuring cosyntropin test. Based on our experience, we conclude that when suspecting a diagnosis of checkpoint inhibitor induced adrenal insufficiency, we should start by checking random cortisol and ACTH value. A standard 250 mcg cosyntropin test should not be used solely to completely rule out this diagnosis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.