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Review
. 2009 Jan 1;14(1):19-44.
doi: 10.2741/3229.

AMPK: Lessons from transgenic and knockout animals

Benoit Viollet  1 , Yoni Athea, Remi Mounier, Bruno Guigas, Elham Zarrinpashneh, Sandrine Horman, Louise Lantier, Sophie Hebrard, Jocelyne Devin-Leclerc, Christophe Beauloye, Marc Foretz, Fabrizio Andreelli, Renee Ventura-Clapier, Luc Bertrand
Affiliations
Review

AMPK: Lessons from transgenic and knockout animals

Benoit Viollet et al. Front Biosci (Landmark Ed). .

Abstract

AMP-activated protein kinase (AMPK), a phylogenetically conserved serine/threonine protein kinase, has been proposed to function as a fuel gauge to monitor cellular energy status in response to nutritional environmental variations. AMPK system is a regulator of energy balance that, once activated by low energy status, switches on ATP-producing catabolic pathways (such as fatty acid oxidation and glycolysis), and switches off ATP-consuming anabolic pathways (such as lipogenesis), both by short-term effect on phosphorylation of regulatory proteins and by long-term effect on gene expression. Numerous observations obtained with pharmacological activators and agents that deplete intracellular ATP have been supportive of AMPK playing a role in the control of energy metabolism but none of these studies have provided conclusive evidence. Relatively recent developments in our understanding of precisely how AMPK complexes might operate to control energy metabolism is due in part to the development of transgenic and knockout mouse models. Although there are inevitable caveats with genetic models, some important findings have emerged. In the present review, we discuss recent findings obtained from animal models with inhibition or activation of AMPK signaling pathway.

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Figures

Figure 1
Figure 1. AMPKα1α2LS−/− mice are resistant to AICAR hypoglycemic effect
AMPKα1α2LS−/− mice deleted for both AMPK catalytic subunit in the liver were obtained by crossing liver-specific AMPKα2−/− mice with AMPKα1−/− mice. AICAR tolerance test were performed on overnight fasted mice injected intraperitonealy with 0.25 g/kg of AICAR and tail blood was collected at 0, 20, 40, 60 and 80 min for determination of glucose concentration using a glucometer. **P <0.001, ***P <0.0001 vs. control mice by unpaired, two-tailed Student t test.
Figure 2
Figure 2. Effect of hepatic AMPKα2-CA expression on glycolytic and lipogenic gene expression in the liver of 6hours fasted ob/ob mice
Adenovirus expressing AMPKα2-CA (Ad α2-CA) or β-gal (Ad β-gal) were injected in ob/ob and control mice and gene expression was analyzed 48 hours post-injection. Each value indicates the amount of mRNA with respect to that in 6 hours fasted control C57Bl6J mice, arbitrarily defined as 1. Fold increase is indicated below each graph column. *P < 0.05, **P < 0.01, #P < 0.005, ##P < 0.001 vs. control mice and $P < 0.05, §P < 0.005, §§P < 0.001 vs. ob/ob Ad β-gal-injected mice. L-PK, L-pyruvate kinase; GK, glucokinase; S14, Spot 14 ; SREBP-1, sterol regulatory element– binding protein-1; ChREBP, carbohydrate response element–binding protein; ACC, acetyl CoA-carboxylase; FAS, fatty acid synthase; SCD-1, stearoyl-CoA desaturase-1; GPAT, glycerol-3-phosphate acyltransferase.
Figure 3
Figure 3. Wheel-running parameters for wild type (Control), and AMPKα2 (AMPKα2−/−) deficient mice
Parameters are averaged per week. (A) distance per day in km. (B) maximal running speed in m per min. (C) number of runs per day. (D) distance per run in meters. Running wheels were connected to a DC generator allowing slight loading of the wheel (27.10−3 N m at mean maximal speed) and continuous recording of the output voltage of the DC generator on a PC computer. Instantaneous speed was calculated from the voltage and the resistive load on the DC generator and allowed calculating the distance. These daily values were averaged over each week for each animal. Total distance divided by number of times (number of runs) gave the distance per run.
Figure 4
Figure 4. Role of AMPKα2 in skeletal muscle mitochondrial function
Substrate utilization by mitochondria were determined in permeabilized fibers of soleus (A) and plantaris (B) muscles of sedentary (SED) and active (ACT) AMPK 2 −/− (KO) mice and littermate (CT) controls. Respiration rates were measured during the cumulative addition of substrates in saponin-skinned cardiac fibers of control and AMPKα2−/− mice. VO2: rate of O2 consumption in μmol·min−1·g dw−1. G3P: glycerol-3-phosphate, Mal: malate, Oct: octanoylcarnitine, Pyr: pyruvate, Glu: glutamate. * p<0.05 vs. control mice.
Figure 5
Figure 5. Control of cardiac metabolism during normoxia (A), ischemia (B) and reperfusion (C)
Under normoxic condition, ATP production comes from fatty acids and glucose oxidation. Fatty acids is the privileged substrate (70%) used by the heart, its β-oxidation inhibiting glucose oxidation via the Randle cycle. Under ischemic condition, glycolysis becomes the sole ATP-providing pathway. AMPK plays the role of fuel gauge during this phase. Being activated by the resulting increase in AMP/ATP ratio, AMPK is able to promote Glut-4 translocation and PFK-1 stimulation via PFK-2 activation. By stimulating glycolysis, AMPK is expected to be protective for the heart during ischemia. During early reperfusion, the still existing activated AMPK phosphorylates and inactivates ACC, inducing fatty acid entry into mitochondria. This favors fatty acid oxidation to become again the principal source for ATP production (80–90%). The concomitant stimulation of glycolysis and fatty acid oxidation should induce the uncoupling of glycolysis and glucose oxidation, and, so, the detrimental production of protons.
Figure 5
Figure 5. Control of cardiac metabolism during normoxia (A), ischemia (B) and reperfusion (C)
Under normoxic condition, ATP production comes from fatty acids and glucose oxidation. Fatty acids is the privileged substrate (70%) used by the heart, its β-oxidation inhibiting glucose oxidation via the Randle cycle. Under ischemic condition, glycolysis becomes the sole ATP-providing pathway. AMPK plays the role of fuel gauge during this phase. Being activated by the resulting increase in AMP/ATP ratio, AMPK is able to promote Glut-4 translocation and PFK-1 stimulation via PFK-2 activation. By stimulating glycolysis, AMPK is expected to be protective for the heart during ischemia. During early reperfusion, the still existing activated AMPK phosphorylates and inactivates ACC, inducing fatty acid entry into mitochondria. This favors fatty acid oxidation to become again the principal source for ATP production (80–90%). The concomitant stimulation of glycolysis and fatty acid oxidation should induce the uncoupling of glycolysis and glucose oxidation, and, so, the detrimental production of protons.
Figure 5
Figure 5. Control of cardiac metabolism during normoxia (A), ischemia (B) and reperfusion (C)
Under normoxic condition, ATP production comes from fatty acids and glucose oxidation. Fatty acids is the privileged substrate (70%) used by the heart, its β-oxidation inhibiting glucose oxidation via the Randle cycle. Under ischemic condition, glycolysis becomes the sole ATP-providing pathway. AMPK plays the role of fuel gauge during this phase. Being activated by the resulting increase in AMP/ATP ratio, AMPK is able to promote Glut-4 translocation and PFK-1 stimulation via PFK-2 activation. By stimulating glycolysis, AMPK is expected to be protective for the heart during ischemia. During early reperfusion, the still existing activated AMPK phosphorylates and inactivates ACC, inducing fatty acid entry into mitochondria. This favors fatty acid oxidation to become again the principal source for ATP production (80–90%). The concomitant stimulation of glycolysis and fatty acid oxidation should induce the uncoupling of glycolysis and glucose oxidation, and, so, the detrimental production of protons.
Figure 6
Figure 6. Effect of AMPKα2 or LKB1 deletion on glycogen content and lactate production in normoxic and ischemic hearts
Hearts were from control (+/+) and knock-out (−/−) mice and perfused under normoxic (open bars) or ischemic (solid bars) conditions. Values are the means ± SE of at least 5 hearts. *P < 0.05 vs. control mice.
Figure 7
Figure 7. Proposed model for the role of AMPK in the hypothalamic control of food intake
The activation of AMPK in the hypothalamus during starvation and its inactivation upon refeeding are mediated by nutritional changes in circulating hormones and nutrients. Ghrelin and adiponectin, which stimulate food intake, activate hypothalamic AMPK, whereas glucose, insulin, leptin and presumably resistin, which are known to inhibit food intake, inhibit it. Once activated, AMPK phosphorylates and inactivates ACC. The expected consequences are elevated malonyl-CoA concentration, leading to subsequent inhibition of mitochondrial fatty acid oxidation, and increased level of LCFA-CoA. The hypothalamic integration of these signals results in opposite changes in orexigenic/anorexigenic neuropeptides expression and subsequent modification of food intake. The underlying mechanism(s) upstream and downstream AMPK remain to be identified. ACC, acetyl-CoA carboxylase; ACS, acyl-CoA synthetase; AMPK, AMP-activated protein kinase; CPT-1, carnitine palmitoyl transferase 1; FAS, fatty acid synthase; MCD, malonyl-CoA decarboxylase; mTOR, mammalian target of rapamycin.
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