The current obesity pandemic results from a physiological imbalance in which energy intake chronically exceeds energy expenditure (EE), and prevention and treatment strategies remain generally ...ineffective. Approaches designed to increase EE have been informed by decades of experiments in rodent models designed to stimulate adaptive thermogenesis, a long-term increase in metabolism, primarily induced by chronic cold exposure. At the cellular level, thermogenesis is achieved through increased rates of futile cycling, which are observed in several systems, most notably the regulated uncoupling of oxidative phosphorylation from ATP generation by uncoupling protein 1, a tissue-specific protein present in mitochondria of brown adipose tissue (BAT). Physiological activation of BAT and other organ thermogenesis occurs through β-adrenergic receptors (AR), and considerable effort over the past 5 decades has been directed toward developing AR agonists capable of safely achieving a net negative energy balance while avoiding unwanted cardiovascular side effects. Recent discoveries of other BAT futile cycles based on creatine and succinate have provided additional targets. Complicating the current and developing pharmacological-, cold-, and exercise-based methods to increase EE is the emerging evidence for strong physiological drives toward restoring lost weight over the long term. Future studies will need to address technical challenges such as how to accurately measure individual tissue thermogenesis in humans; how to safely activate BAT and other organ thermogenesis; and how to sustain a negative energy balance over many years of treatment.
BACKGROUNDMirabegron is a β3-adrenergic receptor (β3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that β3-AR agonists could also improve ...obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODSWe treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by 18F-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test.RESULTSChronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion.CONCLUSIONThese findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of β3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATIONClinicaltrials.gov NCT03049462.FUNDINGThis work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).
Abstract
Context
Pheochromocytomas/paragangliomas (PPGLs) are neuroendocrine tumors that can secrete norepinephrine (NE). Brown adipose tissue (BAT) activation is mediated through the action of NE on ...β-adrenoceptors (β-ARs). In some malignancies, BAT activation is associated with higher cancer activity.
Objective
To study the relationship between BAT activation and PPGL clinical outcomes.
Design
A retrospective case-control study that included 342 patients with PPGLs who underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography (18F-FDG PET/CT) imaging at the National Institutes of Health (NIH). We excluded all patients with parasympathetic tumors and those who underwent 18F-FDG PET/CT after PPGL resection. Scans of 205 patients were reviewed by 2 blinded nuclear medicine physicians; 16 patients had BAT activation on 18F-FDG PET/CT 7.80%; age 27.50 (15.00–45.50) years; 10 female/6 male; body mass index BMI 24.90 19.60–25.35 kg/m2). From the remaining 189 patients, we selected 36 matched controls (age 34.4 25.4–45.5 years; 21 female/15 male; BMI 25.0 22.0–26.0 kg/m2).
Primary Outcome Measure
Overall survival.
Results
The presence of active BAT on 18F-FDG PET/CT was associated with decreased overall survival when compared with the control group (HRz 5.80; 95% CI, 1.05–32.05; P = 0.02). This association remained significant after adjusting for the SDHB mutation. Median plasma NE in the BAT group was higher than the control group 4.65 vs 0.55 times above the upper limit of normal; P < 0.01. There was a significant association between higher plasma NE levels and mortality in PPGLs in both groups.
Conclusions
Our findings suggest that the detection of BAT activity in PPGL patients is associated with higher mortality. We suggest that BAT activation could either be reflecting or contributing to a state of increased host stress that may predict poor outcome in metastatic PPGL.
Abstract
Context
Patients with mutations of the insulin receptor gene (INSR) have extreme insulin resistance and are at risk for early morbidity and mortality from diabetes complications. A case ...report suggested that thyroid hormone could improve glycemia in INSR mutation in part by increasing brown adipose tissue (BAT) activity and volume.
Objective
To determine if thyroid hormone increases tissue glucose uptake and improves hyperglycemia in INSR mutation.
Design
Single-arm, open-label study of liothyronine.
Setting
National Institutes of Health.
Participants
Patients with homozygous (n = 5) or heterozygous (n = 2) INSR mutation.
Intervention
Liothyronine every 8 hours for 2 weeks (n = 7); additional 6 months’ treatment in those with hemoglobin A1c (HbA1c) > 7% (n = 4).
Outcomes
Whole-body glucose uptake by isotopic tracers; tissue glucose uptake in muscle, white adipose tissue (WAT) and BAT by dynamic 18F fluorodeoxyglucose positron emission tomography/computed tomography; HbA1c.
Results
There was no change in whole-body, muscle, or WAT glucose uptake from baseline to 2 weeks of liothyronine. After 6 months, there was no change in HbA1c (8.3 ± 1.2 vs 9.1 ± 3.0%, P = 0.27), but there was increased whole-body glucose disposal (22.8 ± 4.9 vs 30.1 ± 10.0 µmol/kg lean body mass/min, P = 0.02), and muscle (0.7 ± 0.1 vs 2.0 ± 0.2 µmol/min/100 mL, P < 0.0001) and WAT glucose uptake (1.2 ± 0.2 vs 2.2 ± 0.3 µmol/min/100 mL, P < 0.0001). BAT glucose uptake could not be quantified because of small volume. There were no signs or symptoms of hyperthyroidism.
Conclusion
Liothyronine administered at well-tolerated doses did not improve HbA1c. However, the observed increases in muscle and WAT glucose uptake support the proposed mechanism that liothyronine increases tissue glucose uptake. More selective agents may be effective at increasing tissue glucose uptake without thyroid hormone–related systemic toxicity.
Clinical Trial Registration Number: NCT02457897; https://clinicaltrials.gov/ct2/show/NCT02457897.
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.
Abstract
Context
Patients taking exogenous glucocorticoids are at risk for gastrointestinal (GI) complications, including peptic ulcer disease with perforation and gastric bleeding. However, little ...is known about the GI comorbidity in patients with endogenous hypercortisolemia.
Case Descriptions
We describe six patients with endogenous Cushing syndrome (CS) who developed sudden perforation of colonic diverticula necessitating urgent exploratory laparotomy. Most of these patients shared the following features of CS: skin thinning, severe hypercortisolemia (24-hour urinary free cortisol ≥10 times the upper limit of normal), ectopic secretion of ACTH, and severe hypokalemia. At the time of diagnosis of diverticular perforation (DP), these patients had minimal signs of peritonitis and lacked fever or marked leukocytosis. The diagnosis of DP was established by having a low threshold for obtaining an imaging study for evaluation of nonspecific abdominal pain.
Conclusions
Patients with CS can develop spontaneous surgical abdomen with rapid decompensation within hours. Prompt recognition is critical in the successful treatment of these patients.
We describe six patients with Cushing syndrome who developed spontaneous surgical abdomen from perforation of sigmoid diverticula, suggesting underlying predisposition.
A 36-year-old male patient initially presented with hypertension, tinnitus, bilateral carotid masses, a right jugular foramen, and a periaortic arch mass with an elevated plasma dopamine level but an ...otherwise normal biochemical profile. On surveillance MRI 4 years after initial presentation, he was found to have a 2.2-cm T2 hyperintense lesion with arterial enhancement adjacent to the gallbladder, which demonstrated avidity on
68
Ga-DOTATATE PET/CT and retrospectively on
18
F-FDOPA PET/CT but was non-avid on
18
F-FDG PET/CT. Biochemical work-up including plasma catecholamines, metanephrines, and chromogranin A levels were found to be within normal limits. This lesion was surgically resected and was confirmed to be a paraganglioma (PGL) originating from the gallbladder wall on histopathology. Pheochromocytoma (PHEO) and PGL are rare tumors of the autonomic nervous system. Succinate dehydrogenase subunit D (
SDHD
) pathogenic variants of the succinate dehydrogenase complex are usually involved in parasympathetic, extra-adrenal, multifocal head, and neck PGLs. We report an unusual location of PGL in the gallbladder associated with
SDHD
mutation which could present as a potential pitfall on
18
F-FDOPA PET/CT as its normal excretion occurs through biliary system and gallbladder. This case highlights the superiority of
68
Ga-DOTATATE in comparison to
18
F-FDOPA and
18
F-FDG in the detection of
SDHD
-related parasympathetic PGL.
ClinicalTrials.gov Identifier:
NCT00004847
.
Abstract
Disclosure: J. Schipper: None. Z. Abdul Sater: None.
Since the outbreak of the SARS-CoV-2 pandemic, there have been reports of autoimmune thyroid diseases related to COVID inflection and ...SARS-CoV-2 vaccination. We report a case of SARS-CoV-2 mRNA vaccination (mCoVvax)-induced Graves with retrosternal extension. A 21-year-old Hispanic male with no previous history of thyroid illness presented with a 4-month history of tachycardia, tremors, agitation, unintentional weight loss, night sweats, low-grade fever, and orthopnea that developed 62 days after receiving the first dose of mCoVvax. His physical examination was significant for sinus tachycardia, hypertension, a resting tremor, brisk deep tendon reflexes, and diffuse nonpruritic maculopapular rash. His thyroid gland was diffusely enlarged with an unpalpable lower margin and positive Pemberton sign. TSH was undetectable with elevated Free T4 and Total T3 11.0 (NL 0.8-1.8 ng/dL) and 800 (76-181 ng/dL), respectively. Thyroid-stimulating immunoglobulin (TSI) was 337% (NL<140%), and thyroid peroxidase antibody was 653 IU/mL (NL < 9 IU/mL). Thyroid ultrasound showed a diffusely enlarged thyroid gland with diffusely increased thyroid uptake on technetium thyroid scan (95% and 85% uptake after 6 and 24 hrs, respectively), consistent with Graves’ disease. CT scan of the neck and chest confirmed retrosternal Goiter without tracheal deviation. He was treated with high-dose of Methimazole, Atenolol, and Prednisone. A literature search revealed five cases of Graves’ disease after mCOVvax, all of which did not have a retrosternal extension of the thyroid. Our case represents a rare complication of mCoVvax. Clinicians should consider retrosternal goiter in patients with thyrotoxicosis and orthopnea after mCoVvax exposure.
Presentation: Friday, June 16, 2023
There are conflicting reports on whether familial nonmedullary thyroid cancer is more aggressive than sporadic nonmedullary thyroid cancer. Our aim was to determine if the clinical and pathologic ...characteristics of familial nonmedullary thyroid cancer are different than nonmedullary thyroid cancer.
We compared patients with familial nonmedullary thyroid cancer to a cohort of 53,571 nonmedullary thyroid cancer patients from the Surveillance, Epidemiology, and End Results database.
A total of 78 patients with familial nonmedullary thyroid cancer from 31 kindreds presented at a younger age (P = .04) and had a greater rate of T1 disease (P = .019), lymph node metastasis (P = .002), and the classic variant of papillary thyroid cancer on histology (P < .001) compared with the Surveillance, Epidemiology, and End Results cohort. Patients with ≥3 affected family members presented at a younger age (P = .04), had a lesser female-to-male ratio (P = .04), and had a greater rate of lymph node metastasis (P = .009). Compared with the Surveillance, Epidemiology, and End Results cohort, we found a higher prevalence of lymph node metastasis in familial nonmedullary thyroid cancer index cases (P = .003) but not in those diagnosed by screening ultrasonography (P = .58).
Patients with familial nonmedullary thyroid cancer present at a younger age and have a greater rate of lymph node metastasis. The treatment for familial nonmedullary thyroid cancer should be more aggressive in patients who present clinically and in those who have ≥3 first-degree relatives affected.
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