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Review
. 2016:2016:2754078.
doi: 10.1155/2016/2754078. Epub 2016 Jul 28.

Hypothalamic AMPK as a Regulator of Energy Homeostasis

My Khanh Q Huynh  1 , Ann W Kinyua  1 , Dong Joo Yang  1 , Ki Woo Kim  1
Affiliations
Review

Hypothalamic AMPK as a Regulator of Energy Homeostasis

My Khanh Q Huynh et al. Neural Plast. 2016.

Abstract

Activated in energy depletion conditions, AMP-activated protein kinase (AMPK) acts as a cellular energy sensor and regulator in both central nervous system and peripheral organs. Hypothalamic AMPK restores energy balance by promoting feeding behavior to increase energy intake, increasing glucose production, and reducing thermogenesis to decrease energy output. Besides energy state, many hormones have been shown to act in concert with AMPK to mediate their anorexigenic and orexigenic central effects as well as thermogenic influences. Here we explore the factors that affect hypothalamic AMPK activity and give the underlying mechanisms for the role of central AMPK in energy homeostasis together with the physiological effects of hypothalamic AMPK on energy balance restoration.

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Figures

Figure 1
Figure 1
The structure and regulation of AMPK. AMP-activated protein kinase (AMPK) complexes are heterotrimeric kinase composed of α, β, and γ subunits in a 1 : 1 : 1 ratio. AMPK is specifically activated by AMP and its analogues via allosteric activation. The activity of AMPK is also induced through reversible phosphorylation, especially on Thr-172 residue. Calcium and calmodulin increase the phosphorylation of AMPK through Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) while the elevated AMP : ATP ratio can enhance liver kinase B1 (LKB1) activity. AMPK activation is also regulated by the ubiquitin proteasome system.
Figure 2
Figure 2
Factors modulating hypothalamic AMPK activity. By inducing AMPK phosphorylation, adiponectin, ghrelin, cannabinoids, and glucocorticoids activate hypothalamic AMPK activity. On the other hand, estradiol, leptin, insulin, and glucagon-like peptide-1 (GLP-1) inhibit central AMPK activity by decreasing AMPK phosphorylation. AdipoR1, adiponectin receptor 1; GHSR, growth hormone secretagogue receptor; CaMKKβ, Ca2+/calmodulin-dependent protein kinase kinase β; CB1R, cannabinoid type 1 receptor; ERα, estrogen receptor α; GLP-1R, glucagon-like peptide-1 receptor.
Figure 3
Figure 3
The physiological effects of hypothalamic AMPK. Activated in energy depletion conditions, hypothalamic AMP-activated protein kinase (AMPK) restores energy homeostasis by promoting appetite and reducing energy output. Activated hypothalamic AMPK stimulates the orexigenic neuropeptides leading to enhanced food intake and inhibits anorexigenic neuropeptide suppressing food intake. The mammalian target of rapamycin (mTOR), suppressed by the activation of AMPK, also decreases feeding behavior under the effect of leptin. AMPK activity can induce appetite via the inhibition of malonyl-CoA and activation of carnitine palmitoyltransferase- (CPT-) 1. The inhibition of AMPK on malonyl-CoA can lead to decreased fatty acid synthesis and increased β-oxidation. Furthermore, increased β-oxidation could result in the induction of orexigenic gene expression. Besides that, AMPK activation through the sympathetic nerve can reduce thermogenesis and decrease energy expenditure. Additionally, activated hypothalamic AMPK can lead to enhanced glucose production. AgRP, agouti-related protein; NPY, neuropeptide Y; POMC, proopiomelanocortin; TSC2, tuberous sclerosis complex 2; hVps34, mammalian vacuolar protein sorting 34 homologue; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; Rpa, raphe pallidus; IO, inferior olive; β3AR, β3-adrenergic receptor; UCP1, uncoupling protein 1; PGC1α, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha.
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