Assessment of Acute and Chronic Pharmacological Effects on Energy Expenditure and Macronutrient Oxidation in Humans: Responses to Ephedrine

Evidence of active brown adipose tissue in human adults suggests that this may become a pharmacological target to induce negative energy balance. We have explored whole-body indirect calorimetry to detect the metabolic effects of thermogenic drugs through administration of ephedrine hydrochloride and have assessed ephedrine's merits as a comparator compound in the evaluation of novel thermogenic agents. Volunteers randomly given ephedrine hydrochloride 15 mg QID(n=8)or placebo(n=6)were studied at baseline and after 1-2 and 14-15 days of treatment. We demonstrate that overnight or 23-hour, 2% energy expenditure (EE) and 5% fat (FO) or CHO oxidation effects are detectable both acutely and over 14 days. Compared to placebo, ephedrine increased EE and FO rates overnight (EE 63 kJ day 2, EE 105 kJ, FO 190 kJ, day 14), but not over 23 h. We conclude that modest energy expenditure and fat oxidation responses to pharmacological interventions can be confidently detected by calorimetry in small groups. Ephedrine should provide reliable data against which to compare novel thermogenic compounds.

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Neuronal Protein Tyrosine Phosphatase 1B Deficiency Results in Inhibition of Hypothalamic AMPK and Isoform-Specific Activation of AMPK in Peripheral Tissues

Molecular and Cellular Biology ◽

10.1128/mcb.01914-08 ◽

2009 ◽

Vol 29 (16) ◽

pp. 4563-4573 ◽

Cited By ~ 59

Author(s):

Bingzhong Xue ◽

Thomas Pulinilkunnil ◽

Incoronata Murano ◽

Kendra K. Bence ◽

Huamei He ◽

...

Keyword(s):

Energy Expenditure ◽

Target Genes ◽

Fiber Type ◽

Metabolic Effects ◽

Whole Body ◽

Acid Oxidation ◽

Peripheral Tissues ◽

Leptin Sensitivity ◽

Brown Adipose ◽

Ampk Activity

ABSTRACT PTP1B−/− mice are resistant to diet-induced obesity due to leptin hypersensitivity and consequent increased energy expenditure. We aimed to determine the cellular mechanisms underlying this metabolic state. AMPK is an important mediator of leptin's metabolic effects. We find that α1 and α2 AMPK activity are elevated and acetyl-coenzyme A carboxylase activity is decreased in the muscle and brown adipose tissue (BAT) of PTP1B−/− mice. The effects of PTP1B deficiency on α2, but not α1, AMPK activity in BAT and muscle are neuronally mediated, as they are present in neuron- but not muscle-specific PTP1B−/− mice. In addition, AMPK activity is decreased in the hypothalamic nuclei of neuronal and whole-body PTP1B−/− mice, accompanied by alterations in neuropeptide expression that are indicative of enhanced leptin sensitivity. Furthermore, AMPK target genes regulating mitochondrial biogenesis, fatty acid oxidation, and energy expenditure are induced with PTP1B inhibition, resulting in increased mitochondrial content in BAT and conversion to a more oxidative muscle fiber type. Thus, neuronal PTP1B inhibition results in decreased hypothalamic AMPK activity, isoform-specific AMPK activation in peripheral tissues, and downstream gene expression changes that promote leanness and increased energy expenditure. Therefore, the mechanism by which PTP1B regulates adiposity and leptin sensitivity likely involves the coordinated regulation of AMPK in hypothalamus and peripheral tissues.

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Nesfatin-1 Acts Centrally to Induce Sympathetic Activation of Brown Adipose Tissue and Non-Shivering Thermogenesis

Hormone and Metabolic Research ◽

10.1055/a-0985-4272 ◽

2019 ◽

Vol 51 (10) ◽

pp. 678-685 ◽

Cited By ~ 1

Author(s):

Luka Levata ◽

Riccardo Dore ◽

Olaf Jöhren ◽

Markus Schwaninger ◽

Carla Schulz ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Expenditure ◽

Brown Adipose Tissue ◽

Body Weight Loss ◽

Whole Body ◽

Central Administration ◽

Adrenergic Stimulation ◽

Interscapular Brown Adipose Tissue ◽

Adrenoceptor Antagonist ◽

Brown Adipose

AbstractNesfatin-1 has originally been established as a bioactive peptide interacting with key hypothalamic nuclei and neural circuitries in control of feeding behavior, while its effect on energy expenditure has only recently been investigated. Hence, the aim of this study was to examine whether centrally acting nesfatin-1 can induce β3-adrenergic stimulation, which is a prerequisite for the activation of thermogenic genes and heat release from interscapular brown adipose tissue, key physiological features that underlie increased energy expenditure. This question was addressed in non-fasted mice stereotactically cannulated to receive nesfatin-1 intracerebroventricularly together with peripheral injection of the β3-adrenoceptor antagonist SR 59230 A, to assess whole-body energy metabolism. Using a minimally invasive thermography technique, we now demonstrate that the thermogenic effect of an anorectic nesfatin-1 dose critically depends on β3 adrenergic stimulation, as the co-administration with SR 59230 A completely abolished heat production from interscapular brown adipose tissue and rise in ocular surface temperature, thus preventing body weight loss. Moreover, through indirect calorimetry it could be shown that the anorectic concentration of nesfatin-1 augments overall caloric expenditure. Plausibly, central administration of nesfatin-1 also enhanced the expression of DIO2 and CIDEA mRNA in brown adipose tissue critically involved in the regulation of thermogenesis.

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Energy balance in rats given chronic hormone treatment

British Journal Of Nutrition ◽

10.1079/bjn19890133 ◽

1989 ◽

Vol 61 (3) ◽

pp. 437-444 ◽

Cited By ~ 8

Author(s):

Christopher J. H. Woodward ◽

Peter W. Emery

Keyword(s):

Energy Balance ◽

Energy Expenditure ◽

Insulin Treatment ◽

Statistical Significance ◽

Metabolizable Energy ◽

Fat Free Mass ◽

Whole Body ◽

Interscapular Brown Adipose Tissue ◽

Total Enzyme Activity ◽

Brown Adipose

1. Sprague–Dawley rats were injected for 16 d with long-acting insulin, and energy balance was calculated using the comparative carcass technique. Two experiments were carried out with females (starting weights 150 and 90 g respectively), and one with males (starting weight 150 g). In a fourth experiment, cytochrome c oxidasc (EC 1.9.3.1) activity was measured as an indicator of the capacity for substrate oxidation.2. Insulin increased weight gain by up to 57% (P < 0.01 for all studies). Metabolizable energy intake (kJ/d) was also consistently higher in the treated groups, by up to 34% (P < 0.01 for all studies). The excess weight gained by the insulin-treated rats was predominantly due to fat deposition.3. Energy expenditure, calculated as the difference between metabolizable intake and carcass energy gain. was expressed on a whole-body basis, or relative to either metabolic body size (kg body-weight0.75) or fat-free mass. Insulin consistently raised energy expenditure, regardless of the method of expression, but this change reached statistical significance in only two of the nine comparisons.4. Cytochrome c oxidase activity was not affected by insulin treatment in either interscapular brown adipose tissue or gastrocnemius muscle. In liver, total enzyme activity (U/tissue) was increased from 2928 (se 162) in the controls to 3940 (se 294) in the treated group (P < 0.02), but specific activity (U/mg protein) was unchanged.5. It is concluded that, despite causing substantial hyperphagia, insulin treatment only slightly increases energy expenditure in rats. The costs of increased tissue deposition may account for this change.

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Fat feeding causes widespread in vivo insulin resistance, decreased energy expenditure, and obesity in rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1986.251.5.e576 ◽

1986 ◽

Vol 251 (5) ◽

pp. E576-E583 ◽

Cited By ~ 79

Author(s):

L. H. Storlien ◽

D. E. James ◽

K. M. Burleigh ◽

D. J. Chisholm ◽

E. W. Kraegen

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Energy Expenditure ◽

Metabolic Rate ◽

Brown Adipose Tissue ◽

Whole Body ◽

Brown Adipose ◽

Glucose Output ◽

Fat Feeding

High levels of dietary fat may contribute to both insulin resistance and obesity in humans but evidence is limited. The euglycemic clamp technique combined with tracer administration was used to study insulin action in vivo in liver and individual peripheral tissues after fat feeding. Basal and nutrient-stimulated metabolic rate was assessed by open-circuit respirometry. Adult male rats were pair-fed isocaloric diets high in either carbohydrate (69% of calories; HiCHO) or fat (59% of calories; HiFAT) for 24 +/- 1 days. Feeding of the HiFAT diet resulted in a greater than 50% reduction in net whole-body glucose utilization at midphysiological insulin levels (90-100 mU/l) due to both reduced glucose disposal and, to a lesser extent, failure to suppress liver glucose output. Major suppressive effects of the HiFAT diet on glucose uptake were found in oxidative skeletal muscles (29-61%) and in brown adipose tissue (BAT; 78-90%), the latter accounting for over 20% of the whole-body effect. There was no difference in basal metabolic rate but thermogenesis in response to glucose ingestion was higher in the HiCHO group. In contrast to their reduced BAT weight, the HiFAT group accumulated more white adipose tissue, consistent with reduced energy expenditure. HiFAT feeding also resulted in major decreases in basal and insulin-stimulated conversion of glucose to lipid in liver (26-60%) and brown adipose tissue (88-90%) with relatively less effect in white adipose (0-43%). We conclude that high-fat feeding results in insulin resistance due mainly to effects in oxidative skeletal muscle and BAT.(ABSTRACT TRUNCATED AT 250 WORDS)

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Effects of neuromuscular electrical stimulation on energy expenditure and postprandial metabolism in healthy men

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2021-0361 ◽

2021 ◽

Author(s):

Yung-Chih Chen ◽

Russell G Davies ◽

Aaron Hengist ◽

Harriet A Carroll ◽

Oliver J Perkin ◽

...

Keyword(s):

Electrical Stimulation ◽

Energy Expenditure ◽

Neuromuscular Electrical Stimulation ◽

Metabolic Health ◽

Carbohydrate Oxidation ◽

Metabolic Effects ◽

Whole Body ◽

Healthy Men ◽

Potential Strategy ◽

Postprandial Insulin

It is unclear whether NeuroMuscular Electrical Stimulation (NMES) has meaningful metabolic effects when users have the opportunity to self-select the intensity to one that can be comfortably tolerated. Nine healthy men aged 28 ± 9 y (mean ± SD) with a body mass index 22.3 ± 2.3 kg/m2 completed 3 trials involving a 2-h oral glucose tolerance test whilst, in a randomized counterbalanced order, (1) sitting motionless (SIT), (2) standing motionless (STAND); and (3) sitting motionless with NMES of quadriceps and calves at a self-selected tolerable intensity. Mean (95% confidence interval [CI]) total energy expenditure was greater in the NMES trial (221 [180–262] kcal/2 h) and STAND trial (178 [164–191] kcal/2 h) than during SIT (159 [150–167] kcal/2 h) (both, p < 0.05). This was primarily driven by an increase in carbohydrate oxidation in the NMES and STAND trials compared to SIT (p < 0.05). Postprandial insulin iAUC was lower in both NMES and STAND compared to SIT (16.4 [7.7–25.1], 17 [7–27] & 22.6 [10.8–34.4] nmol·120 min/L, respectively; both, p < 0.05). Compared with sitting, both NMES and STAND increased energy expenditure and whole-body carbohydrate oxidation and reduced postprandial insulin concentrations in healthy men, with more-pronounced effects seen with NMES. Self-selected NMES is a potential strategy to improve metabolic health. This trial is registered at ClinicalTrials.gov (ID: NCT04389736). Novelty • NMES at a comfortable intensity enhances energy expenditure & carbohydrate oxidation and reduces postprandial insulinemia. • Thus, self-selected NMES represents a potential strategy to improve metabolic health.

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Brown Adipose Tissue and Its Role in Insulin and Glucose Homeostasis

International Journal of Molecular Sciences ◽

10.3390/ijms22041530 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1530

Author(s):

Katarzyna Maliszewska ◽

Adam Kretowski

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Energy Expenditure ◽

Brown Adipose Tissue ◽

Glucose Homeostasis ◽

Uncoupling Protein ◽

Negative Energy ◽

Metabolic Complications ◽

Brown Adipose ◽

Prevalence Of Obesity

The increased worldwide prevalence of obesity, insulin resistance, and their related metabolic complications have prompted the scientific world to search for new possibilities to combat obesity. Brown adipose tissue (BAT), due to its unique protein uncoupling protein 1 (UPC1) in the inner membrane of the mitochondria, has been acknowledged as a promising approach to increase energy expenditure. Activated brown adipocytes dissipate energy, resulting in heat production. In other words, BAT burns fat and increases the metabolic rate, promoting a negative energy balance. Moreover, BAT alleviates metabolic complications like dyslipidemia, impaired insulin secretion, and insulin resistance in type 2 diabetes. The aim of this review is to explore the role of BAT in total energy expenditure, as well as lipid and glucose homeostasis, and to discuss new possible activators of brown adipose tissue in humans to treat obesity and metabolic disorders.

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Disparate effects of fenfluramine on thermogenesis in brown adipose tissue in the rat

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y92-026 ◽

1992 ◽

Vol 70 (2) ◽

pp. 214-218 ◽

Cited By ~ 4

Author(s):

Stephanie W. Y. Ma ◽

Edward Preston

Keyword(s):

Blood Flow ◽

Adipose Tissue ◽

Ambient Temperature ◽

Brown Adipose Tissue ◽

Metabolic Effects ◽

Whole Body ◽

Flow Measurements ◽

Brown Adipose ◽

Cardiac Ventricle ◽

Blood Flow Measurements

It has been suggested that fenfluramine, a clinically used appetite suppressant, can also promote weight loss by augmenting energy expenditure, as indicated by increased whole-body O2 consumption [Formula: see text] and mitochondrial GDP binding in brown adipose tissue (BAT) of fenfluramine-treated rats. To further investigate a possible involvement of BAT in the drug's metabolic effects, 113Sn-labelled microspheres were injected into the left cardiac ventricle of conscious rats 70–80 min after intraperitoneal delivery of 20 mg/kg fenfluramine (DL-mixture) or saline vehicle. At 28 °C ambient temperature, fenfluramine augmented resting whole-body [Formula: see text] and increased the microsphere entrapment in BAT, indicating enhanced blood flow and metabolism. At 20 °C ambient temperature, the expected increase in BAT blood flow associated with nonshivering thermogenesis was observed in control rats, but in fenfluramine-treated rats the increase in BAT blood flow was severely attenuated, and [Formula: see text] and body temperature were reduced. The stimulatory effect of fenfluramine on BAT metabolism was not prevented by urethane anesthesia but did not occur if the tissue was denervated. These blood flow measurements corroborate previous reports, based on GDP-binding assays, that fenfluramine treatment can augment thermogenesis in BAT by effects mediated through the innervation of the tissue. However, the data also indicate that this calorigenic effect is dependent on ambient temperature being near thermoneutrality and that in a cool environment the drug inhibits BAT thermogenesis.Key words: fenfluramine, brown adipose tissue, thermogenesis.

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MGAT2 deficiency and vertical sleeve gastrectomy have independent metabolic effects in the mouse

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00376.2014 ◽

2014 ◽

Vol 307 (11) ◽

pp. E1065-E1072 ◽

Cited By ~ 9

Author(s):

Joram D. Mul ◽

Denovan P. Begg ◽

April M. Haller ◽

Josh W. Pressler ◽

Joyce Sorrell ◽

...

Keyword(s):

Body Weight ◽

Sleeve Gastrectomy ◽

Glucose Metabolism ◽

Energy Expenditure ◽

Lipid Synthesis ◽

Metabolic Effects ◽

Whole Body ◽

Vertical Sleeve Gastrectomy ◽

Beneficial Effects ◽

Reduced Body

Vertical sleeve gastrectomy (VSG) is currently one of the most effective treatments for obesity. Despite recent developments, the underlying mechanisms that contribute to the metabolic improvements following bariatric surgery remain unresolved. VSG reduces postprandial intestinal triglyceride (TG) production, but whether the effects of VSG on intestinal metabolism are related to metabolic outcomes has yet to be established. The lipid synthesis enzyme acyl CoA:monoacylglycerol acyltransferase-2 ( Mogat2; MGAT2) plays a crucial role in the assimilation of dietary fat in the intestine and in regulation of adiposity stores as well. Given the phenotypic similarities between VSG-operated and MGAT2-deficient animals, we reasoned that this enzyme could also have a key role in mediating the metabolic benefits of VSG. However, VSG reduced body weight and fat mass and improved glucose metabolism similarly in whole body MGAT2-deficient ( Mogat2−/−) mice and wild-type littermates. Furthermore, along with an increase in energy expenditure, surgically naive Mogat2−/− mice had altered macronutrient preference, shifting preference away from fat and toward carbohydrates, and increased locomotor activity. Collectively, these data suggest that the beneficial effects of VSG on body weight and glucose metabolism are independent of MGAT2 activity and rather that they are separate from the effects of MGAT2 deficiency. Because MGAT2 inhibitors are proposed as a pharmacotherapeutic option for obesity, our data suggest that, in addition to increasing energy expenditure, shifting macronutrient preference away from fat could be another important mechanism by which these compounds could contribute to weight loss.

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Grains of paradise (Aframomum melegueta) extract activates brown adipose tissue and increases whole-body energy expenditure in men

British Journal Of Nutrition ◽

10.1017/s0007114512005715 ◽

2013 ◽

Vol 110 (4) ◽

pp. 733-738 ◽

Cited By ~ 40

Author(s):

Jun Sugita ◽

Takeshi Yoneshiro ◽

Takuya Hatano ◽

Sayuri Aita ◽

Takeshi Ikemoto ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Expenditure ◽

Human Subjects ◽

Whole Body ◽

Negative Group ◽

Oral Ingestion ◽

Positive Group ◽

Bat Activity ◽

Brown Adipose ◽

Body Energy

Brown adipose tissue (BAT) is responsible for cold- and diet-induced thermogenesis, and thereby contributes to the control of whole-body energy expenditure (EE) and body fat content. BAT activity can be assessed by fluoro-2-deoxyglucose (FDG)-positron emission tomography (PET) in human subjects. Grains of paradise (GP, Aframomum melegueta), a species of the ginger family, contain pungent, aromatic ketones such as 6-paradol, 6-gingerol and 6-shogaol. An alcohol extract of GP seeds and 6-paradol are known to activate BAT thermogenesis in small rodents. The present study aimed to examine the effects of the GP extract on whole-body EE and to analyse its relation to BAT activity in men. A total of nineteen healthy male volunteers aged 20–32 years underwent FDG-PET after 2 h of exposure to cold at 19°C with light clothing. A total of twelve subjects showed marked FDG uptake into the adipose tissue of the supraclavicular and paraspinal regions (BAT positive). The remaining seven showed no detectable uptake (BAT negative). Within 4 weeks after the FDG-PET examination, whole-body EE was measured at 27°C before and after oral ingestion of GP extract (40 mg) in a single-blind, randomised, placebo-controlled, crossover design. The resting EE of the BAT-positive group did not differ from that of the BAT-negative group. After GP extract ingestion, the EE of the BAT-positive group increased within 2 h to a significantly greater (P< 0·01) level than that of the BAT-negative group. Placebo ingestion produced no significant change in EE. These results suggest that oral ingestion of GP extract increases whole-body EE through the activation of BAT in human subjects.

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Natural Extracts to Augment Energy Expenditure as a Complementary Approach to Tackle Obesity and Associated Metabolic Alterations

Biomolecules ◽

10.3390/biom11030412 ◽

2021 ◽

Vol 11 (3) ◽

pp. 412

Author(s):

Marina Reguero ◽

Marta Gómez de Cedrón ◽

Guillermo Reglero ◽

José Carlos Quintela ◽

Ana Ramírez de Molina

Keyword(s):

Adipose Tissue ◽

Energy Expenditure ◽

Metabolic Stress ◽

Whole Body ◽

Acid Oxidation ◽

Nucleotide Polymorphisms ◽

Metabolic Alterations ◽

Natural Extracts ◽

Brown Adipose ◽

Critical Components

Obesity is the epidemic of the 21st century. In developing countries, the prevalence of obesity continues to rise, and obesity is occurring at younger ages. Obesity and associated metabolic stress disrupt the whole-body physiology. Adipocytes are critical components of the systemic metabolic control, functioning as an endocrine organ. The enlarged adipocytes during obesity recruit macrophages promoting chronic inflammation and insulin resistance. Together with the genetic susceptibility (single nucleotide polymorphisms, SNP) and metabolic alterations at the molecular level, it has been highlighted that key modifiable risk factors, such as those related to lifestyle, contribute to the development of obesity. In this scenario, urgent therapeutic options are needed, including not only pharmacotherapy but also nutrients, bioactive compounds, and natural extracts to reverse the metabolic alterations associated with obesity. Herein, we first summarize the main targetable processes to tackle obesity, including activation of thermogenesis in brown adipose tissue (BAT) and in white adipose tissue (WAT-browning), and the promotion of energy expenditure and/or fatty acid oxidation (FAO) in muscles. Then, we perform a screening of 20 natural extracts (EFSA approved) to determine their potential in the activation of FAO and/or thermogenesis, as well as the increase in respiratory capacity. By means of innovative technologies, such as the study of their effects on cell bioenergetics (Seahorse bioanalyzer), we end up with the selection of four extracts with potential application to ameliorate the deleterious effects of obesity and the chronic associated inflammation.

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