Sex Differences in the Metabolic Effects of Testosterone in Sheep

Adiposity is regulated in a sexually divergent manner. This is partly due to sex steroids, but the differential effects of androgens in males and females are unclear. We investigated effects of testosterone on energy balance in castrated male (n = 6) and female sheep (n = 4), which received 3 × 200 mg testosterone implants for 2 wk or blank implants (controls). Temperature probes were implanted into retroperitoneal fat and skeletal muscle. Blood samples were taken to measure metabolites and insulin. In males, muscle and fat biopsies were collected to measure uncoupling protein (UCP) mRNA and phosphorylation of AMP-activated protein kinase and Akt. Testosterone did not change food intake in either sex. Temperature in muscle was higher in males than females, and testosterone reduced heat production in males only. In fat, however, temperature was higher in the castrate males compared with females, and there was no effect of testosterone treatment in either sex. Preprandial glucose levels were lower, but nonesterified fatty acids were higher in females compared with males, irrespective of testosterone. In males, the onset of feeding increased UCP1 and UCP3 mRNA levels in skeletal muscle, without an effect of testosterone. During feeding, testosterone reduced glucose levels in males only but did not alter the phosphorylation of AMP-activated protein kinase or Akt in muscle. Thus, testosterone maintains lower muscle and fat temperatures in males but not females. The mechanism underlying this sex-specific effect of testosterone is unknown but may be due to sexual differentiation of the brain centers controlling energy expenditure.

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Expression of Uncoupling Protein 3 and GLUT4 Gene in Skeletal Muscle of Preterm Newborns: Possible Control by AMP-Activated Protein Kinase

Pediatric Research ◽

10.1203/01.pdr.0000242301.64555.e2 ◽

2006 ◽

Vol 60 (5) ◽

pp. 569-575 ◽

Cited By ~ 8

Author(s):

Petr Brauner ◽

Pavel Kopecky ◽

Pavel Flachs ◽

Ondrej Kuda ◽

Jaroslav Vorlicek ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Uncoupling Protein ◽

Uncoupling Protein 3 ◽

Amp Activated Protein Kinase ◽

Preterm Newborns

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Whole body metabolic effects of prolonged endurance training in combination with erythropoietin treatment in humans: a randomized placebo controlled trial

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00269.2013 ◽

2013 ◽

Vol 305 (7) ◽

pp. E879-E889 ◽

Cited By ~ 20

Author(s):

Britt Christensen ◽

Birgitte Nellemann ◽

Mads S. Larsen ◽

Line Thams ◽

Peter Sieljacks ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Endurance Training ◽

Exercise Capacity ◽

Uncoupling Protein ◽

Metabolic Effects ◽

Whole Body ◽

Mrna Levels ◽

Healthy Humans ◽

Ucp2 Mrna

Erythropoietin (Epo) administration improves aerobic exercise capacity and insulin sensitivity in renal patients and also increases resting energy expenditure (REE). Similar effects are observed in response to endurance training. The aim was to compare the effects of endurance training with erythropoiesis-stimulating agent (ESA) treatment in healthy humans. Thirty-six healthy untrained men were randomized to 10 wk of either: 1) placebo ( n = 9), 2) ESA ( n = 9), 3) endurance training ( n = 10), or 4) ESA and endurance training ( n = 8). In a single-blinded design, ESA/placebo was injected one time weekly. Training consisted of biking for 1 h at 65% of wattmax three times per week. Measurements performed before and after the intervention were as follows: body composition, maximal oxygen uptake, insulin sensitivity, REE, and palmitate turnover. Uncoupling protein 2 (UCP2) mRNA levels were assessed in skeletal muscle. Fat mass decreased after training ( P = 0.003), whereas ESA induced a small but significant increase in intrahepatic fat ( P = 0.025). Serum free fatty acid (FFA) levels and palmitate turnover decreased significantly in response to training, whereas the opposite pattern was found after ESA. REE corrected for lean body mass increased in response to ESA and training, and muscle UCP2 mRNA levels increased after ESA ( P = 0.035). Insulin sensitivity increased only after training ( P = 0.011). In conclusion: 1) insulin sensitivity is not improved after ESA treatment despite improved exercise capacity, 2) the calorigenic effects of ESA may be related to increased UCP2 gene expression in skeletal muscle, and 3) training and ESA exert opposite effects on lipolysis under basal conditions, increased FFA levels and liver fat fraction was observed after ESA treatment.

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AMP-activated protein kinase activates transcription of the UCP3 and HKII genes in rat skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00278.2002 ◽

2002 ◽

Vol 283 (6) ◽

pp. E1239-E1248 ◽

Cited By ~ 64

Author(s):

James Stoppani ◽

Audrey L. Hildebrandt ◽

Kei Sakamoto ◽

David Cameron-Smith ◽

Laurie J. Goodyear ◽

...

Keyword(s):

Skeletal Muscle ◽

Blood Glucose ◽

Protein Kinase ◽

Energy Demand ◽

Uncoupling Protein ◽

Hexokinase Ii ◽

Arterial Infusion ◽

Ampk Signaling ◽

Lactate Levels ◽

Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) has recently emerged as a key signaling protein in skeletal muscle, coordinating the activation of both glucose and fatty acid metabolism in response to increased cellular energy demand. To determine whether AMPK signaling may also regulate gene transcription in muscle, rats were given a single subcutaneous injection (1 mg/g) of the AMP analog 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside (AICAR). AICAR injection activated ( P < 0.05) AMPK-α2 (∼2.5-fold) and transcription of the uncoupling protein-3 (UCP3, ∼4-fold) and hexokinase II (HKII, ∼10-fold) genes in both red and white skeletal muscle. However, AICAR injection also elicited ( P < 0.05) an acute drop (60%) in blood glucose and a sustained (2-h) increase in blood lactate, prompting concern regarding the specificity of AICAR on transcription. To maximize AMPK activation in muscle while minimizing potential systemic counterregulatory responses, a single-leg arterial infusion technique was employed in fully conscious rats. Relative to saline-infused controls, single-leg arterial infusion of AICAR (0.125, 0.5, and 2.5 μg · g−1 · min−1for 60 min) induced a dose-dependent increase (2- to 4-fold, P < 0.05) in UCP3 and HKII transcription in both red and white skeletal muscle. Importantly, AICAR infusion activated transcription only in muscle from the infused leg and had no effect on blood glucose or lactate levels. These data provide evidence that AMPK signaling is linked to the transcriptional regulation of select metabolic genes in skeletal muscle.

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Orally Induced Hyperthyroidism Regulates Hypothalamic AMP-Activated Protein Kinase

Nutrients ◽

10.3390/nu13124204 ◽

2021 ◽

Vol 13 (12) ◽

pp. 4204

Author(s):

Valentina Capelli ◽

Carmen Grijota-Martínez ◽

Nathalia R. V. Dragano ◽

Eval Rial-Pensado ◽

Johan Fernø ◽

...

Keyword(s):

Adipose Tissue ◽

Protein Kinase ◽

Energy Homeostasis ◽

Uncoupling Protein ◽

Core Body Temperature ◽

Metabolic Effects ◽

Central Administration ◽

Treatment Protocols ◽

Brown Adipose ◽

Amp Activated Protein Kinase

Besides their direct effects on peripheral metabolic tissues, thyroid hormones (TH) act on the hypothalamus to modulate energy homeostasis. However, since most of the hypothalamic actions of TH have been addressed in studies with direct central administration, the estimation of the relative contribution of the central vs. peripheral effects in physiologic conditions of peripheral release (or administration) of TH remains unclear. In this study we used two different models of peripherally induced hyperthyroidism (i.e., T4 and T3 oral administration) to assess and compare the serum and hypothalamic TH status and relate them to the metabolic effects of the treatment. Peripheral TH treatment affected feeding behavior, overall growth, core body temperature, body composition, brown adipose tissue (BAT) morphology and uncoupling protein 1 (UCP1) levels and metabolic activity, white adipose tissue (WAT) browning and liver metabolism. This resulted in an increased overall uncoupling capacity and a shift of the lipid metabolism from WAT accumulation to BAT fueling. Both peripheral treatment protocols induced significant changes in TH concentrations within the hypothalamus, with T3 eliciting a downregulation of hypothalamic AMP-activated protein kinase (AMPK), supporting the existence of a central action of peripheral TH. Altogether, these data suggest that peripherally administered TH modulate energy balance by various mechanisms; they also provide a unifying vision of the centrally mediated and the direct local metabolic effect of TH in the context of hyperthyroidism.

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Epinephrine and AICAR-induced PGC-1α mRNA expression is intact in skeletal muscle from rats fed a high-fat diet

AJP Cell Physiology ◽

10.1152/ajpcell.00410.2011 ◽

2012 ◽

Vol 302 (12) ◽

pp. C1772-C1779 ◽

Cited By ~ 14

Author(s):

Bruce C. Frier ◽

Zhongxiao Wan ◽

Deon B. Williams ◽

Amanda L. Stefanson ◽

David C. Wright

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

High Fat Diet ◽

Camp Response Element Binding ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

High Fat ◽

Peroxisome Proliferator Activated Receptor ◽

Male Wistar Rats ◽

Amp Activated Protein Kinase

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis and is controlled, at least in part, through AMP-activated protein kinase and p38-dependent pathways. There is evidence demonstrating that activation of these kinases and induction of PGC-1α in skeletal muscle are regulated by catecholamines. The purpose of the present study was to determine if consumption of a high-fat diet (HFD) impairs epinephrine and 5-aminoimidazole-4-carboxamide-1β-d-ribofuranoside (AICAR) signaling and induction of PGC-1α in rat skeletal muscle. Male Wistar rats were fed chow or a HFD for 6 wk and then given a weight-adjusted bolus injection of epinephrine (20, 10, or 5 μg/100 g body wt sc) or saline, and triceps muscles were harvested 30 min (signaling) or 2 and 4 h (gene expression) postinjection. Despite blunted increases in p38 phosphorylation, the ability of epinephrine to induce PGC-1α was intact in skeletal muscle from HFD-fed rats and was associated with normal increases in activation of PKA and phosphorylation of cAMP response element-binding protein, reputed mediators of PGC-1α expression. The attenuated epinephrine-mediated increase in p38 phosphorylation was independent of increases in MAPK phosphatase 1. At 2 h following AICAR treatment (0.5 g/kg body wt sc), AMP-activated protein kinase and acetyl-CoA carboxylase phosphorylation were similar in skeletal muscle from chow- and HFD-fed rats. Surprisingly, AICAR-induced increases in PGC-1α mRNA levels were greater in skeletal muscle from HFD-fed rats. Our results demonstrate that the ability of epinephrine and AICAR to induce PGC-1α remains intact in skeletal muscle from HFD-fed rats. These results question the existence of reduced β-adrenergic responsiveness in diet-induced obesity and demonstrate that increases in p38 phosphorylation are not required for induction of PGC-1α in muscle from obese rats.

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Energy-sensing and signaling by AMP-activated protein kinase in skeletal muscle

Journal of Applied Physiology ◽

10.1152/jappl.2001.91.3.1017 ◽

2001 ◽

Vol 91 (3) ◽

pp. 1017-1028 ◽

Cited By ~ 251

Author(s):

W. W. Winder

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Muscle Contraction ◽

Glucose Uptake ◽

Endurance Training ◽

Uncoupling Protein ◽

Energy Charge ◽

Oxidative Enzymes ◽

Energy Sensing ◽

Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) is emerging as an important energy-sensing/signaling system in skeletal muscle. This kinase is activated allosterically by 5′-AMP and inhibited allosterically by creatine phosphate. Phosphorylation of AMPK by an upstream kinase, AMPK kinase (also activated allosterically by 5′-AMP), results in activation. It is activated in both rat and human muscle in response to muscle contraction, the extent of activation depending on work rate and muscle glycogen concentration. AMPK can also be activated chemically in resting muscle with 5-aminoimidazole-4-carboxamide-riboside, which enters the muscle and is phosphorylated to form ZMP, a nucleotide that mimics the effect of 5′-AMP. Once activated, AMPK is hypothesized to phosphorylate proteins involved in triggering fatty acid oxidation and glucose uptake. Evidence is also accumulating for a role of AMPK in inducing some of the adaptations to endurance training, including the increase in muscle GLUT-4, hexokinase, uncoupling protein 3, and some of the mitochondrial oxidative enzymes. It thus appears that AMPK has the capability of monitoring intramuscular energy charge and then acutely stimulating fat oxidation and glucose uptake to counteract the increased rates of ATP utilization during muscle contraction. In addition, this system may have the capability of enhancing capacity for ATP production when the muscle is exposed to endurance training.

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Metabolic effects of mitochondrial uncoupling in murine skeletal muscle: Essential role of AMP-activated protein kinase in metabolic improvements of UCP1-transgenic mice?

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-0032-1330816 ◽

2012 ◽

Vol 120 (10) ◽

Author(s):

M Ost ◽

A Voigt ◽

S Keipert ◽

J Dokas ◽

S Klaus

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Transgenic Mice ◽

Essential Role ◽

Metabolic Effects ◽

Mitochondrial Uncoupling ◽

Murine Skeletal Muscle ◽

Amp Activated Protein Kinase

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UCP-3 expression in skeletal muscle: effects of exercise, hypoxia, and AMP-activated protein kinase

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2000.279.3.e622 ◽

2000 ◽

Vol 279 (3) ◽

pp. E622-E629 ◽

Cited By ~ 96

Author(s):

Min Zhou ◽

Bao-Zhen Lin ◽

Sean Coughlin ◽

Gino Vallega ◽

Paul F. Pilch

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Uncoupling Protein ◽

Fold Increase ◽

Treadmill Running ◽

Mitochondrial Transporter ◽

Edl Muscle ◽

Amp Activated Protein Kinase ◽

Carnitine Palmitoyltransferase 1

Uncoupling protein 3 (UCP-3), a member of the mitochondrial transporter superfamily, is expressed primarily in skeletal muscle where it may play a role in altering metabolic function under conditions of fuel depletion caused, for example, by fasting and exercise. Here, we show that treadmill running by rats rapidly (30 min) induces skeletal muscle UCP-3 mRNA expression (sevenfold after 200 min), as do hypoxia and swimming in a comparably rapid and substantial fashion. The expression of the mitochondrial transporters, carnitine palmitoyltransferase 1 and the tricarboxylate carrier, is unaffected under these conditions. Hypoxia and exercise-mediated induction of UCP-3 mRNA result in a corresponding four- to sixfold increase in rat UCP-3 protein. We treated extensor digitorum longus (EDL) muscle with 5′-amino-4-imidazolecarboxamide ribonucleoside (AICAR), a compound that activates AMP-activated protein kinase (AMPK), an enzyme known to be stimulated during exercise and hypoxia. Incubation of rat EDL muscle in vitro for 30 min with 2 mM AICAR causes a threefold increase in UCP-3 mRNA and a 1.5-fold increase of UCP-3 protein compared with untreated muscle. These data are consistent with the notion that activation of AMPK, presumably as a result of fuel depletion, rapidly regulates UCP-3 gene expression.

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