Inhibition of AMPK in the regulation of food intake

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Recently, AMPK has emerged as a regulator of appetite. Indeed, hypothalamic AMPK is now recognized not only as a nutrient and glucose sensor in the central nervous system (CNS) but also as a key regulator of appetite. Because the brain has an extremely high metabolic rate and is a high lipid-containing tissue, the distribution of the AMPK isoforms throughout its various areas was considered as an exciting area of research. Turnley and coworkers first reported the cellular distribution of AMPK isoforms in mouse CNS (Turnley et al., 1999). They demonstrated that these are widely expressed in neurons and in activated astrocytes. In addition, several groups showed that AMPK isoforms are expressed in hypothalamus and hindbrain, both areas controlling food intake (Kola, 2008). Studies pertaining to pharmacological or genetic activation as well as inhibition of hypothalamic AMPK lead to a better knowledge of hypothalamic AMPK function as a regulator of food intake. It was first recognized that hypothalamic AMPK activation by AICAR infusion into the third ventricle significantly increased food intake (Andersson et al., 2004). Confirming this first study, expression of dominant negative AMPK in the hypothalamus was reported to be sufficient to reduce food intake and body weight, whereas hypothalamic expression of constitutively active AMPK isoform increased both (Minokoshi et al., 2004). In contrast with these previous studies, some conflicting data came from rodent models, especially a2 catalytic subunit specific knock out in hypothalamic Agouti-related peptide (AgRP) neurons or in hypothalamic pro-opiomelanocortin (POMC) neurons. Indeed, in contrast to what could be expected from the data previously published, AMPK-a2 specific deletion in AgRP neurons did not change food intake nor energy expenditure whereas mice were lean. Furthermore, AMPK-a2 specific deletion in POMC neurons unexpectedly increased body weight and adiposity (Claret et al., 2007). To explain some of these surprising data, it was argued that AICAR or Compound C (as used previously in many studies) were not specific of AMPK pathway and that genetically modified mice models may provide new insights into hypothalamic AMPK functions. In this regard, study from Claret and coworkers clearly suggests that loss of AMPK in orexigenic (AgRP) neurons leads to reduced body weight whereas lost of this enzyme in anorexigenic (POMC) neurons leads to increased body weight. Importantly, electrophysiological studies showed that leptin or insulin action are both preserved in AMPKa2-deficient POMC or AgRP neurons. In consequence, this paper challenged the concept of hypothalamic AMPK as a general sensor and integrator of energy homeostasis in the mediobasal hypothalamus.

Hypothalamic AMPK is regulated by various metabolic signals coming from the periphery (Ahima and Antwi, 2008). It is now well accepted that fasting results in activation of AMPK whereas re-feeding inhibits AMPK activity in multiple hypothalamic regions in mice (Kola, 2008). Specific effects of nutrients and hormones on hypothalamic AMPK activity have been investigated by different groups. Peripheral or central hyperglycaemia is known to inhibit AMPK in all brain areas controlling appetite (such as the arcuate nucleus, the ventro- and dorso-mediobasal hypothalamus, the paraventricular nucleus and the lateral hypothalamus (Kim et al., 2004b; Minokoshi et al., 2004). In contrast, hypothalamic AMPK activity was increased (with greater food intake as a consequence) during insulin-induced hypoglycemia or by inhibition of intracellular glucose utilization (administration of 2-deoxyglucose (2-DG)) (Han et al., 2005; Kim et al., 2004b). These data indicate that intraneuronal glucose concentration is a key modulator of hypothalamic AMPK activity. In order to dissociate the respective effects of glucose and insulin on hypothalamic AMPK activity, i.c.v. insulin infusion can be used to study the effects of insulin without any changes in glucose concentration. It has been demonstrated in this way that insulin inhibits hypothalamic AMPK activity (Minokoshi et al., 2004). In consequence, hyperinsulinaemia and/or hyperglycaemia are now recognized as potent inhibitors of hypothalamic AMPK while hypoglycemia is an activator of this enzyme.

Leptin is a key hormone in the communication between energy stores and the brain. In contrast to what is observed in skeletal muscle, leptin decreases hypothalamic AMPK activity (Minokoshi et al., 2002). Similarly, chronic calorie excess, as observed in diet-induced obese mice, reduced hypothalamic AMPK activity (Martin et al., 2006) probably by the inhibitory effects of combined hyperinsulinaemia, hyperglycaemia and increased secreted leptin. Presumably, leptin promotes loss of body weight by enhancing fat oxidation in peripheral tissues and by decreasing food intake, suggesting that leptin has tissue-specific effects. It is not known if muscular AMPK activation by leptin and concomitant reduction of hypothalamic AMPK activity by leptin are supported by different AMPK isoforms. However, as discussed above, the hypothesis that hypothalamic AMPK could be a key mediator for the control of appetite by leptin has been recently challenged when a normal response to leptin  has been described in selective AMPKa2-deficient POMC or AgRP neurons (Claret et al., 2007). Interestingly, it has been shown that like leptin, ciliary neurotrophic factor (CNTF) also suppresses hypothalamic AMPK signaling and reduces food intake (Steinberg et al., 2006b). Importantly, despite the similarities in signaling between leptin and CNTF, CNTF-mediated suppression of hypothalamic AMPK is maintained in diet-induced obesity, whereas the effects of leptin on AMPK signaling are blunted. Thus, the capacity of CNTF to bypass leptin resistance highlights its potential role in the therapeutic treatment of obesity.

AMPK activity is regulated by cellular energetic status, which can be summarized by the intracellular AMP/ATP ratio. Any modification of glucose and/or lipids availability has consequences on AMPK activity. C75 is a fatty acid synthase (FAS) inhibitor which causes weight loss and anorexia. This effect is linked to increased neuronal ATP content by C75 and reduced level of the phosphorylated AMPKa subunit in the hypothalamus (Kim et al., 2004a). Anorectic effect induced by C75 is based on decreased phosphorylation of cAMP response element-binding protein (CREB) in the arcuate nucleus and subsequent reduction in NPY expression (Kim et al., 2004a). Similarly, a-lipoic acid, a cofactor of mitochondrial enzymes that possesses antioxidative, antidiabetic and anorectic properties, inhibits AMPK activity in the hypothalamus (Kim et al., 2004b).

Taking together the effects of nutrients, hormones and compounds described above, it can be postulated that hypothalamic AMPK is a key sensor of whole-body energy status and regulates fuel availability and appetite. Nevertheless, many questions have to be solved. The molecular mechanisms involved in the regulation of food intake by hypothalamic AMPK are not clearly understood. It can be noticed that changes in hypothalamic activity AMPK may contribute to modifications of arcuate neuropeptide expression. Thus, reduction of hypothalamic AMPK activity (by glucose, leptin, insulin, C75, a-lipoic acid and melanocortin 4 receptor agonists) suppresses expression of orexigenic neuropeptides, NPY and AgRP in arcuate nucleus. In contrast, increase in hypothalamic AMPK activity (by hypoglycemia, ghrelin, cannabinoids and adiponectin) enhances the expression of orexigenic NPY and AgRP in arcuate nucleus and melanin-concentrating hormone in the lateral hypothalamus (Minokoshi et al., 2004). In additional studies, it was shown that hypothalamic AMPK and melanocortin pathways are interrelated. Indeed, melanocortin 4 receptor agonists decrease hypothalamic AMPK activity whereas melanocortin receptor antagonists (as AgRP) increase hypothalamic AMPK (Kola, 2008). In these cases, it is difficult to understand if AMPK activity is regulated by AgRP or melanocortin signaling independently of neuronal AMP/ATP ratio changes. Lastly, beyond unspecific effects of AICAR or Compound C, rodent models overexpressing or deleted for hypothalamic AMPK provide evidence of changes of AMPK activity and food intake. However, the extent of physiological relevance of these models could be discussed.