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Aim: Pharmacological stimulation of human brown adipose tissue (BAT) has been hindered by ineffective activation or undesirable off‐target effects. Oral administration of the maximal allowable dose of mirabegron (200 mg), a β3‐adrenergic receptor (β3‐AR) agonist, has been effective in stimulating BAT thermogenesis and whole‐body energy expenditure. However, this has been accompanied by undesirable cardiovascular effects. Therefore, we hypothesized that combining mirabegron with a β1‐AR antagonist could suppress these unwanted effects and increase the stimulation of the β3‐AR and β2‐AR in BAT. Methods: We performed a randomized crossover trial (NCT04823442) in 8 lean men. Mirabegron (200 mg) was administered orally with or without the β1‐AR antagonist bisoprolol (10 mg). Dynamic [11C]‐acetate and 2‐deoxy‐2‐[18F]fluoro‐d‐glucose PET/CT scans were performed sequentially after oral administration of mirabegron ± bisoprolol. Results: Compared to room temperature, mirabegron alone increased BAT oxidative metabolism (0.84 ± 0.46 vs. 1.79 ± 0.91 min−1, p = 0.0433), but not when combined with bisoprolol. The metabolic rate of glucose in BAT, measured using [18F]FDG PET, was significantly higher with mirabegron than mirabegron with bisoprolol (24 ± 10 vs. 16 ± 8 nmol/g/min, p = 0.0284). Bisoprolol inhibited the mirabegron‐induced increase in systolic blood pressure and heart rate. Conclusion: The administration of bisoprolol decreases the adverse cardiovascular effects of mirabegron. However, the provided dose also blunted the mirabegron‐stimulated increase in BAT lipolysis, thermogenesis, and glucose uptake. The attenuation in BAT blood flow induced by the large dose of bisoprolol may have limited BAT thermogenesis. [ABSTRACT FROM AUTHOR]

Purpose: Determine if dynamic contrast enhanced (DCE) ‐MRI and/or 68 gallium 1,4,7,10‐tetraazacyclododecane N, N′, N″, N‴‐tretraacetic acid (68Ga‐DOTA) positron emission tomography (PET) can assess perfusion in rat brown adipose tissue (BAT). Evaluate changes in perfusion between cold‐stimulated and heat‐inhibited BAT. Determine if the 11C‐acetate pharmacokinetic model can be constrained with perfusion information to improve assessment of BAT oxidative metabolism. Methods: Rats were split into three groups. In group 1 (N = 6), DCE‐MRI with gadobutrol was compared directly to 68Ga‐DOTA PET following exposure to 10 °C for 48 h. 11C‐Acetate PET was also performed to assess oxidation. In group 2 (N = 4), only 68Ga‐DOTA PET was acquired following exposure to 10 °C for 48 h. Finally, in group 3 (N = 10), perfusion was assessed with DCE‐MRI in rats exposed to 10 °C or 30 °C for 48 h, and oxidation was measured with 11C‐acetate. Perfusion was quantified with a two‐compartment pharmacokinetic model, while oxidation was assessed by a four‐compartment model. Results: DCE‐MRI and 68Ga‐DOTA PET provided similar perfusion measures, but a decrease in the perfusion signal was noted with longer imaging sessions. Exposure to 10 °C or 30 °C did not affect the perfusion measures, but the 11C‐acetate signal increased in BAT at 10 °C. Without prior information about blood volume, the 11C‐acetate compartment model overestimated blood volume and underestimated oxidation in 10 °C BAT. Conclusion: Precise assessment of oxidation via 11C‐acetate PET requires prior information about blood volume which can be obtained by DCE‐MRI or 68Ga‐DOTA PET. Since perfusion can change rapidly, simultaneous PET‐MRI would be preferred. [ABSTRACT FROM AUTHOR]

Key points Muscle-derived thermogenesis during acute cold exposure in humans consists of a combination of cold-induced increases in skeletal muscle proton leak and shivering., Daily cold exposure results in an increase in brown adipose tissue oxidative capacity coupled with a decrease in the cold-induced skeletal muscle proton leak and shivering intensity., Improved coupling between electromyography-determined muscle activity and whole-body heat production following cold acclimation suggests a maintenance of ATPase-dependent thermogenesis and decrease in skeletal muscle ATPase independent thermogenesis., Although daily cold exposure did not change the fibre composition of the vastus lateralis, the fibre composition was a strong predictor of the shivering pattern evoked during acute cold exposure., Abstract We previously showed that 4 weeks of daily cold exposure in humans can increase brown adipose tissue (BAT) volume by 45% and oxidative metabolism by 182%. Surprisingly, we did not find a reciprocal reduction in shivering intensity when exposed to a mild cold (18°C). The present study aimed to determine whether changes in skeletal muscle oxidative metabolism or shivering activity could account for these unexpected findings. Nine men participated in a 4 week cold acclimation intervention (10°C water circulating in liquid-conditioned suit, 2 h day-1, 5 days week-1). Shivering intensity and pattern were measured continuously during controlled cold exposure (150 min at 4 °C) before and after the acclimation. Muscle biopsies from the m. vastus lateralis were obtained to measure oxygen consumption rate and proton leak of permeabilized muscle fibres. Cold acclimation elicited a modest 21% ( P < 0.05) decrease in whole-body and m. vastus lateralis shivering intensity. Furthermore, cold acclimation abolished the acute cold-induced increase in proton leak. Although daily cold exposure did not change the fibre composition of the m. vastus lateralis, fibre composition was a strong predictor of the shivering pattern evoked during acute cold. We conclude that muscle-derived thermogenesis during acute cold exposure in humans is not only limited to shivering, but also includes cold-induced increases in proton leak. The efficiency of muscle oxidative phosphorylation improves with cold acclimation, suggesting that reduced muscle thermogenesis occurs through decreased proton leak, in addition to decreased shivering intensity as BAT capacity and activity increase. These changes occur with no net difference in whole-body thermogenesis. [ABSTRACT FROM AUTHOR]

The present study was designed to investigate the effects of cold on brown adipose tissue (BAT) energy substrate utilization in vivo using the positron emission tomography tracers [18F]fluorodeoxyglucose (glucose uptake), 14(R,S)-[18F]fluoro-6-thiaheptadecanoic acid [nonesterified fatty acid (NEFA) uptake], and [11C]acetate (oxidative activity). The measurements were performed in rats adapted to 27°C, which were acutely subjected to cold (10°C) for 2 and 6 hours, and in rats chronically adapted to 10°C for 21 days, which were returned to 27°C for 2 and 6 hours. Cold exposure (acutely and chronically) led to increases in BAT oxidative activity, which was accompanied by concomitant increases in glucose and NEFA uptake. The increases were particularly high in cold-adapted rats and largely readily reduced by the return to a warm environment. The cold-induced increase in oxidative activity was meaningfully blunted by nicotinic acid, a lipolysis inhibitor, which emphasizes in vivo the key role of intracellular lipid in BAT thermogenesis. The changes in BAT oxidative activity and glucose and NEFA uptakes were paralleled by inductions of genes involved in not only oxidative metabolism but also in energy substrate replenishment (triglyceride and glycogen synthesis). The capacity of BAT for energy substrate replenishment is remarkable. [ABSTRACT FROM AUTHOR]

Key points Both brown adipose tissue (BAT) and skeletal muscle activation contribute to the metabolic response of acute cold exposure in healthy men even under minimal shivering., Activation of adipose tissue intracellular lipolysis is associated with BAT metabolic response upon acute cold exposure in healthy men., Although BAT glucose uptake per volume of tissue is important, the bulk of glucose turnover during cold exposure is mediated by skeletal muscle metabolic activation even when shivering is minimized., Abstract Cold exposure stimulates the sympathetic nervous system (SNS), triggering the activation of cold-defence responses and mobilizing substrates to fuel the thermogenic processes. Although these processes have been investigated independently, the physiological interaction and coordinated contribution of the tissues involved in producing heat or mobilizing substrates has never been investigated in humans. Using [U-13C]-palmitate and [3-3H]-glucose tracer methodologies coupled with positron emission tomography using 11C-acetate and 18F-fluorodeoxyglucose, we examined the relationship between whole body sympathetically induced white adipose tissue (WAT) lipolysis and brown adipose tissue (BAT) metabolism and mapped the skeletal muscle shivering and metabolic activation pattern during a mild, acute cold exposure designed to minimize shivering response in 12 lean healthy men. Cold-induced increase in whole-body oxygen consumption was not independently associated with BAT volume of activity, BAT oxidative metabolism, or muscle metabolism or shivering intensity, but depended on the sum of responses of these two metabolic tissues. Cold-induced increase in non-esterified fatty acid (NEFA) appearance rate was strongly associated with the volume of metabolically active BAT ( r = 0.80, P = 0.005), total BAT oxidative metabolism ( r = 0.70, P = 0.004) and BAT glucose uptake ( r = 0.80, P = 0.005), but not muscle glucose metabolism. The total glucose uptake was more than one order of magnitude greater in skeletal muscles compared to BAT during cold exposure (674 ± 124 vs. 12 ± 8 μmol min−1, respectively, P < 0.001). Glucose uptake demonstrated that deeper, centrally located muscles of the neck, back and inner thigh were the greatest contributors of muscle glucose uptake during cold exposure due to their more important shivering response. In summary, these results demonstrate for the first time that the increase in plasma NEFA appearance from WAT lipolysis is closely associated with BAT metabolic activation upon acute cold exposure in healthy men. In humans, muscle glucose utilization during shivering contributes to a much greater extent than BAT to systemic glucose utilization during acute cold exposure. [ABSTRACT FROM AUTHOR]

Objective To assess the rapid improvement of insulin sensitivity and β-cell function following biliopancreatic diversion with duodenal switch (BPD-DS) and determine the role played by caloric restriction in these changes. Methods Standard meals were administrated before and on day 3, 4, and 5 after BPD-DS to measure total caloric intake, glucose excursion, insulin sensitivity, and secretion in matched type 2 diabetes and normoglycemic (NG) subjects. In a second set of study, other subjects with type 2 diabetes had the same meal tests prior to and after a 3-day caloric restriction identical to that observed after BPD-DS and then 3 days after actually undergoing BPD-DS. Results Improvement of HOMA-IR occurred at day 3 after BPD-DS in diabetes and after 3 days of caloric restriction. The disposition index (DI) improved rapidly in diabetes after BPD-DS and to a similar extent after caloric restriction. DI was higher and did not change after BPD-DS in NG. Changes in glucagon-like peptide-1, gastric inhibitory peptide, peptide tyrosine tyrosine, ghrelin, and pancreatic polypeptide levels were not associated with modulation of DI in the participants. Conclusions Caloric restriction is the major mechanism underlying the early improvement of insulin sensitivity and β-cell function after BPD-DS in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background Patients with thyroid cancer often need whole-body scintigraphy (WBS) under TSH stimulation after 4–6 weeks withdrawal from levothyroxine (L-T4). Patients often become severely hypothyroid with impaired quality of life. Liothyronine (L-T3) substitution is used empirically to prepare patients; however, no data exist to prove its benefit. Objectives To compare the hypothyroid state in patients receiving either placebo or L-T3 following L-T4 withdrawal and to evaluate the time needed for adequate TSH elevation in preparation for WBS. Methods At the time of L-T4 withdrawal, patients were randomized to receive L-T3 (50 µg qd) or placebo for 3 weeks, after which treatment was stopped. A validated evaluation of hypothyroidism (Billewicz score) was administered in a double-blind fashion every 2 weeks until the WBS. TSH, fT4 and fT3 were measured weekly. Results A total of 20 patients were randomized between September 2003 and May 2005. There was no difference in the Billewicz score at any time between the two groups. Before WBS, both groups were profoundly hypothyroid. TSH at time of WBS was similar in both groups. The time needed to reach a TSH level of more than 30 mUI/l was longer in L-T3 group (mean ± SD: 32 ± 4 days vs. 17 ± 9 days in placebo group, P = 0·006). Conclusion Preparation for WBS with L-T3 does not prevent profound hypothyroidism and delays TSH elevation required for WBS. L-T4 withdrawal alone for 2–3 weeks is simpler and sufficient to allow TSH to reach a level of more than 30 mUI/l in the majority of patients without increasing morbidity from hypothyroidism. [ABSTRACT FROM AUTHOR]

Autotaxin (ATX), an adipose tissue‐derived lysophospholipase, has been involved in the pathophysiology of cardiometabolic diseases. The impact of bariatric surgery on circulating ATX levels is unknown. We examined the short‐ (24 h, 5 days) and longer‐term (6 and 12 months) impact of bariatric surgery; as well as the short‐term effect of caloric restriction (CR) on plasma ATX levels in patients with severe obesity. We measured ATX levels in 69 men and women (mean age: 41 ± 11 years, body mass index: 49.8 ± 7.1 kg/m2), before and after biliopancreatic diversion with duodenal switch surgery (BPD‐DS) as well as in a control group (patients with severe obesity without surgery; n = 34). We also measured ATX levels in seven patients with severe obesity and type 2 diabetes who underwent a 3‐day CR protocol before their BPD‐DS. At baseline, ATX levels were positively associated with body mass index, fat mass, insulin resistance (HOMA‐IR) as well as insulin and leptin levels and negatively with fat‐free mass. ATX concentrations decreased 26.2% at 24 h after BPD‐DS (342.9 ± 152.3 pg/mL to 253.2 ± 68.9 pg/mL, P < 0.0001) and by 16.4% at 12 months after BPD‐DS (342.9 ± 152.3 pg/mL to 286.8 ± 182.6 pg/mL, P = 0.04). ATX concentrations were unchanged during follow‐up in the control group (P = 0.4), and not influenced by short‐term CR. In patients with severe obesity, bariatric surgery induced a rapid and sustained decrease in plasma ATX levels. Acute changes in ATX may not be explained by bariatric surgery‐induced CR. Autotaxin (ATX) is an adipose tissue‐secreted enzyme involved in the pathophysiology of cardiometabolic diseases. The association between obesity and ATX levels is controversial. Whether bariatric surgery and/or caloric restriction influence plasma ATX levels is unknown. We asked whether bariatric surgery and/or caloric restriction influenced plasma ATX levels in patients with severe obesity. We found that bariatric surgery induced a rapid and sustained decrease in plasma ATX levels. Short‐term caloric restriction also did not influence ATX levels. Our results improve our understanding of the factors that influence ATX, a potential therapeutic target for the prevention and management of cardiometabolic diseases. [ABSTRACT FROM AUTHOR]

Aim: Pharmacological stimulation of human brown adipose tissue (BAT) has been hindered by ineffective activation or undesirable off-target effects. Oral administration of the maximal allowable dose of mirabegron (200 mg), a β 3 -adrenergic receptor (β 3 -AR) agonist, has been effective in stimulating BAT thermogenesis and whole-body energy expenditure. However, this has been accompanied by undesirable cardiovascular effects. Therefore, we hypothesized that combining mirabegron with a β 1 -AR antagonist could suppress these unwanted effects and increase the stimulation of the β 3 -AR and β 2 -AR in BAT., Methods: We performed a randomized crossover trial (NCT04823442) in 8 lean men. Mirabegron (200 mg) was administered orally with or without the β 1 -AR antagonist bisoprolol (10 mg). Dynamic [ 11 C]-acetate and 2-deoxy-2-[ 18 F]fluoro-d-glucose PET/CT scans were performed sequentially after oral administration of mirabegron ± bisoprolol., Results: Compared to room temperature, mirabegron alone increased BAT oxidative metabolism (0.84 ± 0.46 vs. 1.79 ± 0.91 min -1 , p = 0.0433), but not when combined with bisoprolol. The metabolic rate of glucose in BAT, measured using [ 18 F]FDG PET, was significantly higher with mirabegron than mirabegron with bisoprolol (24 ± 10 vs. 16 ± 8 nmol/g/min, p = 0.0284). Bisoprolol inhibited the mirabegron-induced increase in systolic blood pressure and heart rate., Conclusion: The administration of bisoprolol decreases the adverse cardiovascular effects of mirabegron. However, the provided dose also blunted the mirabegron-stimulated increase in BAT lipolysis, thermogenesis, and glucose uptake. The attenuation in BAT blood flow induced by the large dose of bisoprolol may have limited BAT thermogenesis., (© 2024 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)