Rediscovery of cold-activated brown adipose tissue (BAT) in humans has boosted research interest in identifying BAT activators for metabolic benefits. Of particular interest are cytokines capable of ...fat browning. Irisin, derived from FNDC5, is an exercise-induced myokine that drives brown-fat-like thermogenesis in murine white fat. Here we explored whether cold exposure is an afferent signal for irisin secretion in humans and compared it with FGF21, a brown adipokine in rodents. Cold exposure increased circulating irisin and FGF21. We found an induction of irisin secretion proportional to shivering intensity, in magnitude similar to exercise-stimulated secretion. FNDC5 and/or FGF21 treatment upregulated human adipocyte brown fat gene/protein expression and thermogenesis in a depot-specific manner. These results suggest exercise-induced irisin secretion could have evolved from shivering-related muscle contraction, serving to augment brown fat thermogenesis in concert with FGF21. Irisin-mediated muscle-adipose crosstalk may represent a thermogenic, cold-activated endocrine axis that is exploitable in obesity therapeutics development.
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•Shivering stimulates irisin secretion in humans•Nonshivering cold exposure increases FGF21, which may be a brown adipokine•Irisin and/or FGF21 upregulates brown-fat-like program in human adipocytes•Exercise may be a shivering mimic exemplifying muscle-fat thermogenic crosstalk
Lee et al. show that, in humans, cold exposure leading to shivering stimulates production of irisin, an exercise-induced myokine, while nonshivering cold exposure increases FGF21. These results suggest exercise-induced irisin secretion could have evolved from shivering-related muscle contraction, serving to augment brown fat thermogenesis in concert with FGF21.
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).
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.
Context:
The contribution of brown adipose tissue (BAT) to the energy balance in humans exposed to sustainable cold has not been completely established, partially because of measurement limitations ...of both BAT activity and energy expenditure (EE).
Objective:
The objective of the study was to characterize the role of BAT activation in cold-induced thermogenesis (CIT).
Design:
This study was a single-blind, randomized crossover intervention.
Setting:
The study was conducted at the National Institutes of Health Clinical Center.
Study Participants:
Thirty-one healthy volunteers participated in the study.
Interventions:
The intervention included mild cold exposure.
Main Outcomes:
CIT and BAT activation were the main outcomes in this study.
Methods:
Overnight EE measurement by whole-room indirect calorimeter at 24°C or 19°C was followed by 2-18F-fluoro-2-deoxy-D-glucose positron emission tomography (PET) scan. After 36 hours, volunteers crossed over to the alternate study temperature under identical conditions. BAT activity was measured in a 3-dimensional region of interest in the upper torso by comparing the uptake at the two temperatures.
Results:
Twenty-four volunteers (14 males, 10 females) had a complete data set. When compared with 24°C, exposure at 19°C resulted in increased EE (5.3 ± 5.9%, P < .001), indicating CIT response and mean BAT activity (10.5 ± 11.1%, P < .001). Multiple regression analysis indicated that a difference in BAT activity (P < .001), age (P = .01), and gender (P = .037) were independent contributors to individual variability of CIT.
Conclusions:
A small reduction in ambient temperature, within the range of climate-controlled buildings, is sufficient to increase human BAT activity, which correlates with individual CIT response. This study uncovers for the first time a spectrum of BAT activation among healthy adults during mild cold exposure not previously recognized by conventional PET and PET-computed tomography methods. The enhancement of cold-induced BAT stimulation may represent a novel environmental strategy in obesity treatment.
Thyroid hormones are important determinants of energy expenditure, and in rodents, adipose tissue affects thyroid hormone homeostasis via leptin signaling. The relationship between thyroid hormones ...and nutritional status in humans has been assessed primarily in drastic dietary or bariatric surgery interventions, while limited information is available on serial assessment of this axis during moderate, prolonged dietary restriction.
To evaluate the effects of moderate dietary restriction on thyroid hormone homeostasis, 47 subjects with a body mass index (BMI) of 25-45 kg/m(2) were enrolled in a longitudinal intervention study; 30 nonoverweight volunteers were also enrolled as controls. Overweight and obese subjects underwent a 12-month individualized dietary intervention aimed at achieving a 5-10% weight loss.
The intervention resulted in a 6.3±0.9 kg (6.5±1.0%) weight loss. At baseline, thyrotropin (TSH) and T3 concentrations correlated significantly with fat mass (R=0.257, p=0.024 and R=0.318, p=0.005, respectively). After weight loss, T3 decreased significantly (from 112.7±3.1 to 101.8±2.6 ng/dL, p<0.001) in the absence of significant changes in TSH or free T4 (fT4). The decrease in serum T3 correlated with the decrease in weight (R=0.294, p<0.001). The T3:fT4 ratio decreased significantly (p=0.02) in individuals who lost >5% body weight.
T3 concentration closely correlates with individual nutritional status, and moderate weight loss results in a decrease in T3 with minimal changes in other thyroid hormone homeostasis parameters. The data suggest that a decrease in peripheral conversion of the prohormone T4 into its hormonally active metabolite T3 is at least in part responsible for the observed changes in thyroid hormone homeostasis.
Context:
Levothyroxine (l-T4) therapy is based on the assumption that the conversion of T4 into T3 provides adequate amounts of active hormone at target tissues. However, in rodents, l-T4 alone does ...not restore a euthyroid state in all tissues. Previous combination l-T4/liothyronine (l-T3) therapy trials focused on quality-of-life endpoints, and limited information is available on the effects on other measures of thyroid hormone action.
Objective:
Our objective was to evaluate the efficacy of thyroid hormone replacement with l-T4 or l-T3 at doses producing equivalent normalization of TSH.
Participants, Design, and Setting:
Fourteen hypothyroid patients participated in this randomized, double-blind, crossover intervention at the National Institutes of Health Clinical Center.
Interventions:
l-T3 or l-T4 were administered thrice daily to achieve a target TSH from 0.5–1.5 mU/liter. Volunteers were studied as inpatients after 6 wk on a stable dose and at the target TSH.
Main Outcome Measures:
Serum thyroid hormones, lipid parameters, and indices of glucose metabolism were evaluated.
Results:
No difference was observed in TSH between l-T3 and l-T4 treatments. l-T3 resulted in significant weight loss l-T4, 70.6 ± 12.5, vs. l-T3, 68.5 ± 11.9 kg (P = 0.009) and in a 10.9 ± 10.0% decrease in total cholesterol (P = 0.002), 13.3 ± 12.1% decrease in low-density lipoprotein-cholesterol (P = 0.002), and an 18.3 ± 28.6% decrease in apolipoprotein B (P = 0.018). No significant differences were observed in high-density lipoprotein-cholesterol, heart rate, blood pressure, exercise tolerance, or insulin sensitivity.
Conclusions:
The substitution of l-T3 for l-T4 at equivalent doses (relative to the pituitary) reduced body weight and resulted in greater thyroid hormone action on the lipid metabolism, without detected differences in cardiovascular function or insulin sensitivity.
Human obesity is an increasing burden worldwide. Lipids stored as metabolic fuel in white adipose tissue (WAT) can be rapidly mobilized through lipolysis. In rodent adipocytes, activation of the ...β3-adrenergic receptors (β3-ARs) leads to lipolysis. The physiological role of the β3-AR in human adipocytes remains controversial due to its reported low expression and previous access only to partial β3-AR agonists. Mirabegron, an FDA-approved drug for overreactive bladder, is a highly-selective human β3-AR agonist. In clinical trials, mirabegron treatment led to activation of human brown adipose tissue (BAT) thermogenesis and increased plasma NEFA’s. Therefore, we investigated if mirabegron directly mediates lipolysis in human white adipocytes. We found similar gene expression of the three β-ARs in human immortalized and primary white adipocytes, with β2-AR being the most expressed, followed by β1-AR and β3-AR. Next, to assess the functionally of the β3-AR in human adipocytes, we established dose-response curves and found that mirabegron increased the release of glycerol, a lipolytic product, in the picomolar range. To identify the molecular mechanism controlling mirabegron-induced lipolysis, we assessed the regulation of key downstream lipolytic proteins. Mirabegron mediated lipolysis by rapidly phosphorylating hormone sensitive lipase (HSL), as well as the mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). Moreover, acute inhibition of either the PKA or MAPK/ERK pathways decreased lipolysis.
In summary, we identify a major role played by the β3-AR in the regulation of human WAT lipolysis. Mirabegron acts as a potent pro-lipolytic effector, signaling through the canonical adrenergic receptor pathway as well as the MAPK/ERK pathway. Due to the comparatively minimal effects previously reported of mirabegron on the cardiovascular system, mirabegron may be the optimal choice for targeted lipid mobilization in human WAT.
Disclosure
C. Cero: None. J.W. Johnson: None. A. O’Mara: None. J.D. Linderman: None. A.M. Cypess: None.
Funding
National Institutes of Health
ObjectiveResting energy expenditure (EE) is a major contributor to the total EE and thus plays an important role in body weight regulation. Adaptive thermogenesis is a major component of EE in ...rodents, but little is known on the effects of exposure of humans to mild and sustainable reduction in environmental temperature.DesignTo characterize the dynamic changes in continuously measured resting EE, substrate utilization, and hormonal axes simultaneously in response to mild reduction in environmental temperature, we performed a cross-over intervention.MethodsTwenty-five volunteers underwent two 12-h recordings of EE in whole room indirect calorimeters at 24 and 19 °C with simultaneous measurement of spontaneous movements and hormonal axes.ResultsExposure to 19 °C resulted in an increase in plasma and urine norepinephrine levels (P<0.0001), and a 5.96% (P<0.001) increase in EE without significant changes in spontaneous physical activity. Exposure to the lower temperature resulted in a significant increase in free fatty acid levels (P<0.01), fasting insulin levels (P<0.05), and a marginal decrease in postprandial glucose levels. A small but significant (P<0.002) increase in serum free thyroxine and urinary free cortisol (P<0.05) was observed at 19 °C.ConclusionsOur observations indicate that exposure to 19 °C, a mild and tolerable cold temperature, results in a predictable increase in EE driven by a sustained rise in catecholamine and the activation of counter-regulatory mechanisms.
β3-adrenergic receptor (AR) agonists are approved to treat only overactive bladder. However, rodent studies suggest that these drugs could have other beneficial effects on human metabolism. We ...performed tissue receptor profiling and showed that the human β3-AR mRNA is also highly expressed in gallbladder and brown adipose tissue (BAT). We next studied the clinical implications of this distribution in twelve healthy men given one-time randomized doses of placebo; the approved dose of 50 mg; and 200 mg of the β3-AR agonist mirabegron. There was a more-than-dose proportional increase in BAT metabolic activity as measured by
F-FDG PET/CT (medians 0.0 vs. 18.2 vs. 305.6 mL*SUVmean*g/mL). Only the 200 mg dose elevated both non-esterified fatty acids (+68%) and resting energy expenditure (+5.8%). Previously undescribed increases in gallbladder size (+35%) and reductions in conjugated bile acids were also discovered. Therefore, besides urinary bladder relaxation, the human β3-AR contributes to WAT lipolysis, BAT thermogenesis, gallbladder relaxation, and bile acid metabolism. This physiology should be considered in the development of more selective β3-AR agonists to treat obesity-related complications.
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