**3.1 Regulation of total calorie intake by AMPK**

AMPK is a serine-threonine kinase that is evolutionarily conserved from yeast to mammals. It is a heterotrimeric protein consisting of an α catalytic subunit as well as β and γ regulatory subunits (**Figure 6**) [4, 5], and it is activated through an allosteric effect of AMP and through phosphorylation of a threonine residue (at position 172) of the α subunit by AMPK kinases such as liver kinase B1 (LKB1) and Ca2+- and calmodulin-dependent protein kinase (CaMKK) [4]. Furthermore, glucose deprivation directly activates AMPK via the glycolytic pathway [5, 44]. CaMKK is activated by an increase in the intracellular Ca2+ concentration induced by hormones or neurotransmitters, whereas LKB1 is activated by an increase in AMP levels and glucose deprivation. AMPK thus acts as a metabolic sensor that integrates multiple metabolic signals including hormones, neurotransmitters, nutrients, and energy charge.

Activation of AMPK suppresses 5′-adenosine triphosphate (ATP)-consuming anabolic pathways and activates ATP-producing catabolic pathways [4, 5]. For example, AMPK inhibits fatty acid synthesis, whereas it activates fatty acid oxidation. Activation of AMPK stimulates fatty acid oxidation, at least in part, by phosphorylation of acetyl coenzyme A (CoA) carboxylase (ACC), a decrease in the amount of malonyl-CoA, and activation of carnitine palmitoyltransferase 1 (CPT1) in mitochondria. We have previously shown that leptin increases fatty acid oxidation by activating AMPK in skeletal muscle both via the hypothalamus-sympathetic nervous system and through direct activation of the leptin receptor in skeletal muscle (**Figure 7**) [6].

#### **Figure 6.**

*Metabolic actions of AMPK. AMPK is a heterotrimeric protein consisting of an α (α1 or α2) catalytic subunit as well as β (β1 or β2) and γ (γ1 to γ3) regulatory subunits. It is activated by an allosteric effect of AMP on the γ subunit and through phosphorylation of the α subunit (at threonine-172) by AMPK kinases such as LKB1 and CaMKK. Activation of AMPK stimulates catabolic pathways and inhibits anabolic pathways of metabolism. Abbreviations not defined in text: ADP, 5′-adenosine diphosphate; GLUT4, glucose transporter 4; UCP3, uncoupling protein 3; PGC-1, peroxisome proliferator-activated receptor γ coactivator-1; PEPCK, phosphoenolpyruvate carboxykinase.*

**11**

**Figure 7.**

*Neural Control of Homeostatic Feeding and Food Selection*

In addition to its metabolic actions in the periphery, AMPK in the hypothalamus

AMPK is necessary for activation of NPY/AgRP neurons in the ARC [47–50]. It is also necessary for activation of upstream neurons that activate NPY/AgRP neurons [51]. AMPK thus plays an important role in the activation of NPY/AgRP neurons

Preferential consumption of high-fat foods among multiple palatable diets has increased worldwide and given rise to a high prevalence of metabolic syndrome, coronary heart disease, diabetes, and cancer [52]. The availability of highly palatable diets such as high-fat and high-sucrose diets promotes overfeeding in humans, with social stress often inducing "carbohydrate craving" [53, 54]. Although macronutrient components are associated with cardiometabolic health, aging, and longevity [55], the mechanisms for macronutrient intake have remained elusive. The consumption of protein and essential amino acids is tightly controlled in animals. Previous studies revealed that forced feeding of animals with a low-protein diet increases total calorie intake, because of compensatory feeding for essential

*Role of AMPK in leptin-induced suppression of feeding and activation of fatty acid oxidation in skeletal muscle. Leptin increases fatty acid oxidation in skeletal muscle through activation of AMPK both directly via the leptin receptor expressed in this tissue as well as indirectly through the hypothalamus-sympathetic nervous* 

*system. Leptin also inhibits food intake through suppression of AMPK in the hypothalamus.*

**3.2 Regulation of carbohydrate selection by AMPK in the hypothalamus**

regulates food intake [7, 44–49]. We found that leptin, glucose, a melanocortin receptor agonist or antagonist, and fasting-refeeding all reduced AMPK activity in several hypothalamic nuclei of mice [7]. A change in hypothalamic AMPK activity was sufficient to alter food intake and body weight (**Figure 7**). Other orexigenic and anorexigenic agents were also found to affect hypothalamic AMPK activity [45]. Downstream targets of AMPK, including ACC/malonyl-CoA and mammalian target of rapamycin (mTOR) pathways, were also found to contribute to regulation of food intake [45]. Suppression of AMPK in the ARC is mediated by the phosphoryla-

*DOI: http://dx.doi.org/10.5772/intechopen.93413*

tion of AMPK via p70S6 kinase [46].

and the regulation of food intake.

*3.2.1 Fasting increases carbohydrate preference in mice*

*Neural Control of Homeostatic Feeding and Food Selection DOI: http://dx.doi.org/10.5772/intechopen.93413*

*New Insights into Metabolic Syndrome*

muscle (**Figure 7**) [6].

**3. Role of the metabolic sensor AMPK in feeding regulation**

AMPK is a serine-threonine kinase that is evolutionarily conserved from yeast to mammals. It is a heterotrimeric protein consisting of an α catalytic subunit as well as β and γ regulatory subunits (**Figure 6**) [4, 5], and it is activated through an allosteric effect of AMP and through phosphorylation of a threonine residue (at position 172) of the α subunit by AMPK kinases such as liver kinase B1 (LKB1) and Ca2+- and calmodulin-dependent protein kinase (CaMKK) [4]. Furthermore, glucose deprivation directly activates AMPK via the glycolytic pathway [5, 44]. CaMKK is activated by an increase in the intracellular Ca2+ concentration induced by hormones or neurotransmitters, whereas LKB1 is activated by an increase in AMP levels and glucose deprivation. AMPK thus acts as a metabolic sensor that integrates multiple metabolic

signals including hormones, neurotransmitters, nutrients, and energy charge.

Activation of AMPK suppresses 5′-adenosine triphosphate (ATP)-consuming anabolic pathways and activates ATP-producing catabolic pathways [4, 5]. For example, AMPK inhibits fatty acid synthesis, whereas it activates fatty acid oxidation. Activation of AMPK stimulates fatty acid oxidation, at least in part, by phosphorylation of acetyl coenzyme A (CoA) carboxylase (ACC), a decrease in the amount of malonyl-CoA, and activation of carnitine palmitoyltransferase 1 (CPT1) in mitochondria. We have previously shown that leptin increases fatty acid oxidation by activating AMPK in skeletal muscle both via the hypothalamus-sympathetic nervous system and through direct activation of the leptin receptor in skeletal

*Metabolic actions of AMPK. AMPK is a heterotrimeric protein consisting of an α (α1 or α2) catalytic subunit as well as β (β1 or β2) and γ (γ1 to γ3) regulatory subunits. It is activated by an allosteric effect of AMP on the γ subunit and through phosphorylation of the α subunit (at threonine-172) by AMPK kinases such as LKB1 and CaMKK. Activation of AMPK stimulates catabolic pathways and inhibits anabolic pathways of metabolism. Abbreviations not defined in text: ADP, 5′-adenosine diphosphate; GLUT4, glucose transporter 4; UCP3, uncoupling protein 3; PGC-1, peroxisome proliferator-activated receptor γ coactivator-1; PEPCK,* 

**3.1 Regulation of total calorie intake by AMPK**

**10**

**Figure 6.**

*phosphoenolpyruvate carboxykinase.*

In addition to its metabolic actions in the periphery, AMPK in the hypothalamus regulates food intake [7, 44–49]. We found that leptin, glucose, a melanocortin receptor agonist or antagonist, and fasting-refeeding all reduced AMPK activity in several hypothalamic nuclei of mice [7]. A change in hypothalamic AMPK activity was sufficient to alter food intake and body weight (**Figure 7**). Other orexigenic and anorexigenic agents were also found to affect hypothalamic AMPK activity [45]. Downstream targets of AMPK, including ACC/malonyl-CoA and mammalian target of rapamycin (mTOR) pathways, were also found to contribute to regulation of food intake [45]. Suppression of AMPK in the ARC is mediated by the phosphorylation of AMPK via p70S6 kinase [46].

AMPK is necessary for activation of NPY/AgRP neurons in the ARC [47–50]. It is also necessary for activation of upstream neurons that activate NPY/AgRP neurons [51]. AMPK thus plays an important role in the activation of NPY/AgRP neurons and the regulation of food intake.
