AMPK as a mediator of hormonal signalling

Lim, Chung Thong; Kola, Blerina; Korbonits, Márta

doi:10.1677/jme-09-0063

Cited by 273 publications

(224 citation statements)

References 133 publications

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“…AMPK, a key fuel-sensing enzyme and a critical regulator of metabolism, mediates the effects of a variety of hormones 17,18 . Phosphorylated-AMPK (p-AMPK) was increased in the proximal intestinal mucosa of NT −/− mice fed standard diet compared with wild type (Extended Data Fig.…”

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confidence: 99%

An obligatory role for neurotensin in high-fat-diet-induced obesity

Song

Zaytseva

et al. 2016

Nature

226

237

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Obesity and its associated comorbidities (e.g., diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually1 and are among the most prevalent and challenging conditions confronting the medical profession2,3. Neurotensin (NT), a 13-amino acid peptide predominantly localized in specialized enteroendocrine (EE) cells of the small bowel4 and released by fat ingestion5, facilitates fatty acid (FA) translocation in rat intestine6, and stimulates growth of various cancers7; the effects of NT are mediated through three known NT receptors (NTR1, 2 and 3)8. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality9; however, a role for NT as a causative factor in these diseases is unknown. Here, we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FA absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3/sortilin. Consistent with the findings in mice, expression of NT in Drosophila midgut EE cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

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confidence: 99%

An obligatory role for neurotensin in high-fat-diet-induced obesity

Song

Zaytseva

et al. 2016

Nature

226

237

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“…When activated, LKB1 phosphorylates and activates AMPKa and its related serine/threonine kinases ( Figure 1) (Hawley et al, 2003;Lizcano et al, 2004;Shaw et al, 2004;Jaleel et al, 2005;Lim et al, 2010). Via the regulation of MARK isoforms and PAR proteins, LKB1 establishes cell polarity (Figure 1) (Spicer et al, 2003;Lizcano et al, 2004).…”

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confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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The liver kinase B1 (LKB1)/adenosine mono-phosphateactivated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/ AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the PeutzJeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.

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“…Eventually, AMPK contributes to an increase in mitochondrial biogenesis in response to chronic energy depletion (Reznick and Shulman 2006). AMPK is also involved in the regulation of food intake through its action on the expression of hypothalamic neuropeptides, with an activation of AMPK leading to increased food intake (Lim et al 2010). Effects of AMPK activation further include modulation of cell cycle, tumor growth suppression, inhibition of proteosynthesis, stimulation of autophagy, ion channel regulation, and many other effects, which are out of the scope of this review.…”

Section: Role Of Ampk In Energy Metabolism and Glucose Homeostasismentioning

confidence: 99%

“…In line with its function as a cellular energy sensor, AMPK has been involved in the metabolic effects of hormones such as leptin, ghrelin, adiponectin, glucocorticoids, insulin, glucagon as well as cannabinoids-all these hormones being involved in regulation of energy metabolism (Lim et al 2010). Although AMPK is apparently present in all tissues (Hardie 2008;Zhang et al 2009), its activation and mode of action seem to be regulated in a tissue-specific manner.…”

Section: Role Of Ampk In Energy Metabolism and Glucose Homeostasismentioning

confidence: 99%

“…Although AMPK is apparently present in all tissues (Hardie 2008;Zhang et al 2009), its activation and mode of action seem to be regulated in a tissue-specific manner. For example, leptin activates AMPK in adipose tissue, SM, and liver but inhibits it in hypothalamus (Lim et al 2010), while adiponectin and anti-diabetic drugs primarily activate the AMPK in the peripheral tissues. Furthermore, there is a number of natural food components believed to exert beneficial effects on health in association with activation of AMPK like plant polyphenols (Um et al 2010) or n-3 long-chain polyunsaturated fatty acids (n-3 PUFA) (Jelenik et al 2010;Kopecky et al 2009).…”

Section: Role Of Ampk In Energy Metabolism and Glucose Homeostasismentioning

confidence: 99%

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Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

et al. 2011

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Strategies to prevent and treat obesity aim to decrease energy intake and/or increase energy expenditure. Regarding the increase of energy expenditure, two key intracellular targets may be considered (1) mitochondrial oxidative phosphorylation, the major site of ATP production, and (2) AMP-activated protein kinase (AMPK), the master regulator of cellular energy homeostasis. Experiments performed mainly in transgenic mice revealed a possibility to ameliorate obesity and associated disorders by mitochondrial uncoupling in metabolically relevant tissues, especially in white adipose tissue (WAT), skeletal muscle (SM), and liver. Thus, ectopic expression of brown fat-specific mitochondrial uncoupling protein 1 (UCP1) elicited major metabolic effects both at the cellular/tissue level and at the whole-body level. In addition to expected increases in energy expenditure, surprisingly complex phenotypic effects were detected. The consequences of mitochondrial uncoupling in WAT and SM are not identical, showing robust and stable obesity resistance accompanied by improvement of lipid metabolism in the case of ectopic UCP1 in WAT, while preservation of insulin sensitivity in the context of high-fat feeding represents the major outcome of muscle UCP1 expression. These complex responses could be largely explained by tissue-specific activation of AMPK, triggered by a depression of cellular energy charge. Experimental data support the idea that (1) while being always activated in response to mitochondrial uncoupling and compromised intracellular energy status in general, AMPK could augment energy expenditure and mediate local as well as whole-body effects; and (2) activation of AMPK alone does not lead to induction of energy expenditure and weight reduction.

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AMPK as a mediator of hormonal signalling

Cited by 273 publications

References 133 publications

An obligatory role for neurotensin in high-fat-diet-induced obesity

An obligatory role for neurotensin in high-fat-diet-induced obesity

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

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