Symptoms and General Pathology

All Conditions

Nutritional and Metabolic Diseases

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Rare Diseases

Syndrome

Obesity

Polycystic Ovary Syndrome

Cysts

Ovarian Cysts

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Gonadal Disorders

Endocrine System Diseases

Chronic Graft Versus Host Disease

Micronutrients

All Drugs and Chemicals

Urological Agents

Vitamins

Ascorbic Acid

Adrenergic Agents

Mirabegron

Adrenergic Agonists

Adrenergic beta-3 Receptor Agonists

Adrenergic beta-Agonists

Neurotransmitter Agents

Vitamin C

Women will take 100mg daily for 4 weeks. Men will take 200mg daily for 4 weeks. The medication is available in 50 mg tablets.

Males will be randomized to take placebo versus active drug (mirabegron). Those taking placebo will take 4 tablets each day to mirror to active group (taking 4 tablets of 50 mg each).

B Complex Plus Vitamin C Tablets

Ashley M Schmitz, C.R.N.P.

Aaron M Cypess, M.D.

For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)

Background:

Brown adipose tissue (BAT) is a type of fat in the body. It may prevent weight gain, improve insulin sensitivity, and reduce fatty liver. Researchers want to see if BAT helps the body burn energy.

Objective:

To learn more about how BAT works to burn energy.

Eligibility:

People ages 18-40 with a body mass index between 18 and 40

Design:

Participants will be screened with:

Medical history

Physical exam

Blood, urine, and heart tests

Dietitian interview

Participants will have an overnight baseline visit. This includes:

Repeats of screening tests

Exercise test

Scans. For one scan, a radioactive substance is injected into the arm.

FSIVGIT: An IV is inserted into veins in the right and left arms. Glucose and insulin are injected in one arm. Blood glucose and insulin levels are measured from the other.

Metabolic suite: Participants stay 18 19 hours in a room that measures their metabolic rate. Monitors on the body measure heart rate, movement, and temperature.

Optional fat biopsy: A small piece of tissue is removed with a needle.

Participants will take 2-4 pills daily for 4 weeks. All women will take the drug mirabegron. Men will be randomly get either the drug or a placebo.

All participants will have a visit after 2 weeks of the pills. They will repeat the screening tests.

Participants will have an overnight visit 2 weeks later. They will repeat the baseline tests.

Participants will keep food and medication diaries.

Participants will have a follow-up visit 2 weeks after stopping the pills. This includes heart tests.

Background issues and controversies

More than ever before, there is a rise in the rates of obesity and diabetes. As opposed to white fat which stores excess calories, brown fat - also known as brown adipose tissue or BAT - consumes this energy to generate heat. In settings of increased food consumption and cold-exposure, studies show that human BAT becomes more active, potentially combatting weight gain. Other emerging evidence indicates that human BAT may be an endocrine organ, releasing hormones into the blood and regulating other organs like skeletal muscle, liver, and the insulin-releasing pancreatic Beta-cell. However, alongside these promising studies are those people who believe that there is not enough BAT in humans to be functionally relevant, and it contributes little to heat generation or overall health.

Purpose/Rationale of the proposed study

One of the principal reasons for skepticism about the ability to utilize human BAT is that there is not very much compared to smaller animals in which BAT activation has shown such promise. Therefore, a critical step is to develop medicines that can grow BAT in people and evaluate what kind of health benefits can be achieved.

Specific objectives

This study will administer the clinically-available beta3-AR agonist, mirabegron (Myrbetriq(R), Astellas Pharma). We will determine whether we can increase BAT volume and activity in people after they have taken this medication daily for four weeks. Our current goal is to see if chronic administration of mirabegron leads to an increase in BAT volume and metabolic activity and if it produces health benefits.

Key elements of what is involved

At the beginning of the study, the participants will undergo a series of tests to determine their baseline amounts of BAT, blood sugar status, and levels of specified hormones. The testing will take place over the course of two to three days while an inpatient on the Metabolic Patient Care Unit at the NIH Clinical Center. Depending on the Cohort, participants will then take the medication alone for four weeks or both the medication and placebo for four weeks each, during which time they will continue their standard daily routines. At two weeks after starting placebo or mirabegron, participants will return for one day for the assessment of any interim changes and to validate safety. At the end of each set of four weeks there will be a second set of inpatient testing over two to three days. Participants will be brought back two weeks after finishing the study for a follow-up safety visit, at which time they will receive an ECG and heart rate monitoring.

Primary outcomes

The primary outcome is either the change in BAT metabolic activity as measured by 18FFDG PET/CT or glucose infusion rate as measured by a hyperinsulinemic euglycemic clamp. Secondary endpoints will examine multiple other factors, including body weight, fat mass, glucose tolerance, changes in levels of hormones, and improved liver function.

The Physiological Responses and Adaptation of Brown Adipose Tissue to Chronic Treatment With Beta3-Adrenergic Receptor Agonists

.Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures and appendices).

Change in brown adipose tissue (BAT) metabolic activity as measured by 18FFDG PET/CT

Change in glucose infusion rate, as measured by the hyperinsulinemic euglycemic clamp

Change in metabolic health parameters including body weight, fat mass, glucose tolerance, changes in levels of hormones, and improved liver function

Changes in glucose infusion rate, as measured by the hyperinsulinemic euglycemic clamp

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Pheochromocytoma

Paraganglioma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Paragangliomas 1

Neuroendocrine Tumor

Neuroepithelioma

Fluorodeoxyglucose F18

Patients will be divided in two groups for statistical analysis:

* patients with detectable BAT by PET-CT (BAT+)
* patients with no detectable BAT by PET-CT (BAT-)

measurement of temperature and microcirculation of the skin overlaying BAT depots in the region of FDG-uptake detected by 18F-FDG PET/CT before and after a cold test

Infrared themrography

Françoise Latil-Plat

Patients affected by pheochromocytoma (PHEO) have brown-adipose tissue (BAT) hyperactivation. They perform, in routine settings, a FDG PET-CT scan. The high metabolic activity of BAT and its ability to consume both glucose and fatty acid suggest that it may have potential as a therapeutic target in the treatment of obesity. However, alternative non-invasive techniques to PET-CT BAT detection still need more validation. Accordingly, our aim will be to measure the temperature and microcirculation of the skin overlaying BAT depots in the region of FDG-uptake detected by 18F-FDG PET/CT before and after a cold test in PHEO patients.

Objectives and Methodology:

* To analyse the change in temperature and microcirculation of the skin overlaying BAT depots in the region of FDG-uptake detected by 18F-FDG PET/CT before and after a cold test in PHEO patients.
* To check the decreased temperature and microcirculatory response after a cold test following resection of the tumor

All the patients affected by will benefit from a:

* clinical: treatments
* biological evaluations: glycemia, triglycerides, total cholesterol, HDL-C, LDL-C, plasma epinephrine and norepinephrine, urine catecholamine
* cutaneous microcirculation by means of Laser Speckle Imaging will be recorded at rest and during a cold test in the supra-clavicular region
* cutaneous microcirculation by means of Laser Doppler Flowmetry will be recorded at rest and during a cold test with one probe in the supra-clavicular region and one probe in umbilical region
* skin temperature by means of infrared thermography will be recorded at rest and during a cold test in the supra-clavicular region

Patients who will have surgery will be investigated before and after one year following resection of the tumor.

Infrared Thermography Associated With Cutaneous Microcirculation for Detection of Brown-adipose Tissue (MICROBAT)

Infrared Thermography Associated With Cutaneous Microcirculation for Detection of Brown-adipose Tissue: Proof of Concept Against PET-CT in Patients Affected by Pheochomocytoma and/or Paraganglioma

Skin temperature in supra-clavicular region will be recorded by infrared thermography (FLIR camera) in basal condition

Skin temperature in supra-clavicular region will be recorded by infrared thermography (FLIR camera) during a cold test (feet in water at 19°C during 20min)

Cutaneous blood flow in supra-clavicular region will be recorded by Laser Speckle Imaging (PeriCam) in basal condition

Cutaneous blood flow in supra-clavicular region will be recorded by Laser Speckle Imaging (PeriCam) during a cold test (feet in water at 19°C during 20min)

18FDG PET-CT will be performed and volume will be segmented by PET/CT Viewer..

18FDG PET-CT will be performed and BAT activity (Standardized Uptake Value (SUV) will be segmented by PET/CT Viewer..

∆ diff TSCR = diff TSCR(month12) - diff TSCR (day0)

∆ diff PU = diff PU (month12) - diff PU (day0)

Centre Hospitalier Henri Duffaut - Avignon

Assistance Publique Hopitaux De Marseille

University of Avignon

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

Trastuzumab

Estrogens

HER2-positive (HER2+) and Estrogen receptor-positive (ER+) breast cancer patients undergoing adjuvant chemotherapy including trastuzumab.

HER2-negative breast cancer patients (HER2-) and Estrogen receptor-positive (ER+) breast cancer patients undergoing adjuvant chemotherapy without trastuzumab.

Both groups recieve standard care as decided by the responsible clinicians at the department of Oncology. The course of the treatment is completely independent from the observations in the present study.

None (Observational study)

Tora Ida Henriksen, MSc., Ph.D.

Laura Thomsen, MSc.

Søren Nielsen, MSc., Ph.D.

The objective of this observational study is to investigate the significance of the HER2 receptor for brown fat activity in humans. Our preliminary data clearly demonstrates that the ErbB signaling pathway, which includes the HER2 receptor, strongly promotes development and function of cultured human BAT cells. The HER2 receptor is a part of the ErbB signaling pathway, and antibodies against thee HER2 receptor are a part of the standard treatment for HER2-positive breast cancer. Therefore, the hypothesis is that the activity of brown fat will be reduced in patients treated with HER2 blocking antibody compared to patients who are not treated with HER2 blocking antibody. The present study simply takes advantage of the treatment protocol to explore the contribution of the HER2 receptor in the development of brown adipose tissue in humans. Participants will complete two testing days, one before and one after their treatment period of approx. one year. On the testing days, identification of brown fat activity will be performed using cooling and infrared thermography. In addition, resting metabolic rate and a glucose tolerance test will be performed. Since presence of active brown adipose tissue in humans is inversely related to obesity, total and visceral fat mass, plasma glucose levels, presence of cardiovascular disease and diabetes status, it is of great importance to investigate the molecular mechanisms for development of brown fat tissue and may lead to discovery of novel strategies to counteract obesity and obesity related disorders.

BACKGROUND:

Breast cancer is the most common cancer among women worldwide, and with increasing survival rates focus on long-term adverse effects of treatment has increased. Weight gain is well documented and common occurrence for many breast cancer patients. Recently, a review reported that 50-96% of women experience weight gain during treatment. Furthermore, many patients report a progressive weight gain in the months and years after treatment and patients rarely return to their pre-diagnosis weight. Moreover, weight gain in breast cancer patients has been linked to a poor prognosis compared to patients without weight gain, and to obesity-related disorders including metabolic syndrome.

Adipose tissue is one of the largest human organs. Two functionally distinct types of adipose tissue exist: white adipose tissue and brown adipose tissue (BAT). While BAT was long thought to be present only in rodents and human infants, it is now clear that active BAT also exists in varying degrees in adult humans. Activated BAT has great capacity for energy consumption and takes up large amounts of blood lipids and glucose to use in thermogenesis, and the presence of active BAT in humans is inversely related to obesity, total and visceral fat mass, plasma glucose levels, presence of cardiovascular disease and diabetes status. In accordance, acute cooling increases energy expenditure compared to thermoneutral conditions and correlates with higher BAT activity. Finding ways to activate BAT in humans is thus an attractive approach to prevent weight gain and ensuing comorbidities.

Human epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for \~15 % of breast cancer cases, and direct inhibition of the HER2 receptor (also called the ErbB2 receptor) is used as standard treatment of HER2-positive breast cancer.

Our preliminary data clearly demonstrates that the ErbB signaling pathway, which includes the HER2 receptor, strongly promotes development and function of cultured human BAT cells and mouse brown adipose tissue. A potential secondary effect of the HER2 receptor blockade used in cancer treatment, is the binding of these inhibitors to ErbB2 receptors in the adipose tissue subsequently affecting downstream signaling pathways that might influence the activity of brown adipose tissue and thereby whole-body metabolism. In support of this hypothesis, weight gain during chemotherapy in HER2-positive breast cancer patients is associated with a decrease in the activity of brown adipose tissue.

Since BAT activity has been suggested as a target to limit weight gain and metabolic disorders, it is of great importance to understand the molecular mechanisms behind BAT recruitment and function in humans. This study will provide insight into the contribution of the HER2 receptor in the development of brown adipose tissue in humans and may thus lead to discovery of novel strategies to counteract obesity and obesity related disorders in breast cancer survivors as well as in the general population.

STUDY SET-UP

Against this background, a prospective cohort study will be performed at the Centre for Physical Activity (CFAS), and the Department of Oncology, both located at Rigshospitalet, Copenhagen, Denmark. A total of 30 patients will be recruited. This includes patients with breast cancer HER2+/ Estrogen receptor (ER)+ treated with the recombinant monoclonal anti-neoplastic antibody combination trastuzumab (n = 15) and BMI and age-matched HER2-/ER+ patients with breast cancer, who are not treated with ErbB2/HER2 receptor blockage, will be used as a control group (n = 15). The treatment is planned and initiated according to standard of care and for clinical reasons. The present study simply takes advantage of the treatment protocol to explore a physiological mechanism, hence participation in the study does not affect the treatment regimen. After cessation of the study period subjects will continue their treatment as prescribed by the oncologists prior to study enrolment.

Patients included in the study will undergo two identical test days; one prior to the treatment and one by the end of the treatment. The study does not include any additional interventions, restrictions, or investigations during the treatment period. For each testing day, the participants will be assessed for body composition (DXA scan) and anthropometrics. This will be followed by a cooling protocol to activate the brown adipose tissue. BAT activity will be measured by infrared thermography. Furthermore, participants will undergo measurements of resting metabolic rate, an oral glucose tolerance (OGTT) test and blood samples.

Provided that the patient fulfilled the inclusion criterion concerning cold activated BAT (see inclusion criteria), they will be invited to a second test day after adjuvant treatment. This test day will be similar to the first, i.e., including anthropometric measurements, a DXA scan, blood samples, an OGTT, indirect calorimetry measurements, a cooling intervention and IRT assessment of BAT activity.

AIM

The objective of this project is thus to investigate the effects of HER2 blockade on human brown adipose tissue activity in HER2+ breast cancer patients as well as associated metabolic parameters.

Secondarily, the study aim to investigate whether a decrease in BAT activity is associated with weight gain or increased fat mass (as assessed by DXA-scan), decreased metabolic rate and changes in metabolic parameters including glycemic control in patients treated with HER2 blocking antibodies.

HYPOTHESIS

The hypothesis is that the activity of brown fat will be reduced in patients treated with HER2 blocking antibody trastuzumab for 17 series amounting to approx. one year of treatment compared to patients who are not treated with trastuzumab.

We will draw blood samples, but not for genetic analysis

The Effects of HER2 Receptor Signaling on Human Brown Fat Activity

The Effects of HER2 Receptor Signaling on Human Brown Fat Activity: A 1-year Prospective Cohort Study in Trastuzumab-treated Breast Cancer Patients Versus HER2 Negative Controls

Difference in cold-induced BAT activity between HER2+ breast cancer patients and HER2- breast cancer controls measured with infrared thermography (temperature difference).

Difference in weight (kilograms) between the HER2+ positive subjects and the HER2 negative controls

Difference in fat mass (kilograms) between the HER2+ positive subjects and the HER2 negative controls

Difference in resting- and cold induced energy expenditure (calories/day) between the HER2+ positive subjects and the HER2 negative controls, by measuring oxygen consumption (VO2) and carbon dioxide production (VCO2) (Indirect calorimetry).

Difference in cold induced energy expenditure (calories/day) between the HER2+ positive subjects and the HER2 negative controls, by measuring oxygen consumption (VO2) and carbon dioxide production (VCO2) (Indirect calorimetry).

Difference in glycemic control between the HER2+ positive subjects and the HER2 negative controls. Examined by an Oral Glucose Tolerance Test measuring insulin (pmol/L)

Difference in glycemic control between the HER2+ positive subjects and the HER2 negative controls. Examined by an Oral Glucose Tolerance Test measuring glucose (mmol/L).

Difference in glycemic control between the HER2+ positive subjects and the HER2 negative controls. Examined by an Oral Glucose Tolerance Test measuring C-peptide (nmol/L).

Rigshospitalet, Denmark

Primary Investigator

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases, Male

Prostatic Diseases

Male Urogenital Diseases

Androgens

Philip J Saylor, MD

Androgen deprivation therapy (ADT) is considered standard of care for prostate cancer. However, changes in the patients metabolism are usually seen as a result of hormone therapy. These changes include increased fat mass, decreased lean mass, weight gain, high blood cholesterol, increased incidence of diabetes, and possibly increased incidence of cardiac events such as heart attack. The researchers of this trial would like to learn if these change in body mass are affected by the presence of brown fat in the body. Brown fat is made up of fat cells that are stored in the body and generate heat to control body temperature. Levels of brown fat are at the highest in newborn babies and decrease over time into adulthood. The researchers of this trial would like to learn more about these changes in metabolism during prostate cancer treatment by studying the changes in brown fat during the first 12 months of hormone therapy.

* Participants will be asked to come into the clinic for additional visits before they begin hormone therapy. The following procedures will be performed: Cold-activated PET/CT scan; body composition DXA scan; blood tests, questionnaires and abdominal fat biopsy.
* During hormone therapy, the participant will return to the clinical once after 3 months, and again after 6 months, to draw blood for laboratory tests.
* After 12 months of hormone therapy, the participant will return to teh clinic to repeat the following procedures: Cold-activated PET/CT scan; body composition DXA scan; blood tests; questionnaires and abdominal fat biopsy.

fine needle aspirate biopsies of subcutaneous fat

Changes in Brown Adipose Tissue Activity In Men Receiving Androgen Deprivation Therapy for Prostate Cancer

Prospective Study of Changes in Brown Adipose Tissue (BAT) Activity in Men Receiving Androgen Deprivation Therapy (ADT) With a GnRH Agonist or Antagonist for Prostate Cancer

To assess the change in cold-activated borwn adipose tissue (BAT) activity upon initiation of GnRH agoinist or antagoinist therapy among men treated for prostate cancer. The primary endpoint is percent change in cold-activated BAT volumne after 12 months of treatment.

To describe interval change in total body weight and body mass during GnRH agonist or antagonist therapy.

To describe interval change in Total body fat mass as determined by body composition dual energy x-ray absorptiometry (DXA) scan during GnRH agonist or antagonist therapy.

To describe interval change in abdominal cross sectional subcutaneous fat area at the L4 verterbral body level during GnRH agonist or antagonist therapy.

To describe interval change in insulin sensitivity (as refelcted by hemoglobin A1C, fasting plasma glucose, and fasting plasma insulin) during GnRH agonist or antagonist therapy.

To describe interval change in serum lipid profile during GnRH agonist or antagonist therapy.

To describe interval change in levels of several markers of BAT regulation \& activity in abdominal subcutaneous fat during GnRH agonist or antagonist therapy.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The Physiological Responses and Adaptation of Brown Adipose Tissue to Chronic Treatment With Beta3-Adrenergic Receptor Agonists	NCT03049462	Polycystic Ovar...	Mirabegron B Complex Plus ...	18 Years - 40 Years	National Institutes of Health Clinical Center (CC)
Infrared Thermography Associated With Cutaneous Microcirculation for Detection of Brown-adipose Tissue (MICROBAT)	NCT04605848	Pheochromocytom... Paraganglioma	Infrared themro...	18 Years - 75 Years	University of Avignon
The Effects of HER2 Receptor Signaling on Human Brown Fat Activity	NCT06222957	Breast Cancer	None (Observati...	18 Years -	Rigshospitalet, Denmark
Changes in Brown Adipose Tissue Activity In Men Receiving Androgen Deprivation Therapy for Prostate Cancer	NCT01226888	Prostate Cancer		-	Massachusetts General Hospital

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