Additional Table 1.
Metabolic sensors and transcriptional regulators that participate in the hypothalamic control of metabolism, the circadian clock and aging
| Nutrient sensor / regulator | Hypothalamus | Circadian clock | Aging | References |
|---|---|---|---|---|
| AMPK | In the POMC and AGRP neuron of the ARC, and the VMH, LH and PVN, responds to glucose, insulin, leptin, adiponectin, vaspin, glucagon controlling several physiological responses, including insulin secretion, corticosterone, glucagon, catecholamines and hepatic glucose production. | AMPK phosphorylates and destabilizes CRY1, thereby regulating the circadian clock. In adipose tissue, it participates in the circadian expression of leptin via the SUCNR1-AMPK/JNK-BMAL1- CLOCK/CEBPa signaling pathway | AMPK activity declines during aging, while its activation improves health span and lifespan in mice | Lamia et al., 2009; Martin-Montalvo et al., 2013; López et al., 2016; Salminen et al., 2016; Villanueva-Carmona et al., 2023 |
| SIRT1 | In the VMH, it plays a role in synchronizing circadian activity through nutrient inputs. Protects against diet-induced obesity by modulating signaling pathways in POMC and SF1 hypothalamic neurons. Modulates the caloric- dependent melanocortin system through the NAD+-SIRTs-FOXO 1 pathway in the hypothalamus. | Regulates the circadian clock by deacetylating BMAL1 and PER2. Activates BMAL1 and CLOCK in the SCN of young mice. | Reduced SIRT1 activity due to declining NAD+ levels during aging leads to mitochondrial dysfunction, which is reversed by increasing NAD+ levels in aged mice. Hypothalamic SIRT1 affects aging and longevity by increasing Ox2r in specific nuclei, suggesting a link between sleep, muscle physiology, and reduced aging phenotype. The effects of calorie restriction (CR) in old mice involve circadian reprogramming of SIRT1 target genes in the liver. | Asher et al., 2008; Nakahata et al., 2008; Jung-Hynes and Ahmad, 2009; Nakahata et al., 2009; Ramadori et al., 2010; Satoh et al., 2010; Ramadori et al., 2011; Gomes et al., 2013; Satoh et al., 2013; Orozco-Solis et al., 2015; Sato et al., 2017; Zhou et al., 2018; Park et al., 2023 |
| SIRT3 | It promotes positive energy balance in male mice by modulating BAT activity via POMC signaling. | The circadian oscillation of NAD+ regulates SIRT3 activity, impacting acetylation and function of mitochondrial enzymes, governing oxidative metabolism. | In stems cells, SIRT3 reverts the effect of aging-oxidative stress in mitochondria activating the anti-oxidative defense system. Deacetylates and activates GSK3B with in turn inhibit TGFB1, blocking age-associate fibrosis. | Brown et al., 2013; Peek et al., 2013; Sundaresan et al., 2016; Quiñones et al., 2021 |
| SIRT6 | In POMC neurons it promotes | SIRT6 plays a role in the circadian | Masri et al., 2014; Tang et al., 2020 | |
| negative energy balance and leptin sensitivity. | regulation of genes involved in fatty acid metabolism. | |||
| SIRT7 | Hepatic SIRT7 deacetylates CRY1 promoting its degradation and controlling circadian gluconeogenesis. | SIRT7 represses mitochondrial folding stress in hippocampal NSC reducing aging- associated reduction of neurogenesis. | Yang et al., 2012; Liu et al., 2019; Wang et al., 2023 | |
| mTOR | mTOR, triggered by L-leucine, regulates food intake and leptin sensitivity, influencing blood pressure and the sympathetic nervous system. Low protein diets inhibit hypothalamic mTOR, enhancing leptin sensitivity. Enhancing mTOR signaling by elimination of TSC1 in POMC neurons reduce energy expenditure, while the reduction of mTOR signaling by eliminating S6K1 in POMC induces hepatic gluconeogenesis while in the AGRP neurons impairs glucose sensitivity. | It rhythmically regulates translation in circadian genes and modulates the circadian clock through the TSC1/2-mTOR pathway. It exhibits rhythmic activity in the SCN and contributes to central clock entrainment. | Aging elevates mTOR activity, diminishing immune responses and lifespan mediated by hematopoietic stem cells. Genetic or pharmacological mTOR inhibition extends lifespan and provides tissue-specific geroprotective effects. | Cota et al., 2006; Castilho et al., 2009; Chen et al., 2009; Harrison et al., 2009; Lamming et al., 2012; Cao et al., 2013; Harlan et al., 2013; Wu et al., 2013; Khapre et al., 2014; Smith et al., 2015; Ramanathan et al., 2018; Wu et al., 2021 |
| PPARγ | Promotes positive energy balance and reduces leptin sensitivity. | PPARy reprograms the circadian transcriptome under HFD. Also controls circadian variation of blood pressure and heart rate. | The elimination of PPARγ in muscle induces progressive insulin resistance in mice. C/G polymorphism is associated with better insulin sensitivity and resistance to oxidative stress. | Hevener et al., 2003; Chakravarthy et al., 2007; Wang et al., 2008; Lu et al., 2011; Ryan et al., 2011; Eckel-Mahan et al., 2013; Long et al., 2014 |
| PI3K | In the VMH, PI3K drives positive energy balance via insulin signaling. In POMC neurons, p110β, a catalytic subunit of PI3K, is crucial for leptin-induced negative energy balance, while in AGRP neurons, it enhances leptin | Participates in the BMAL1/CLOCK recruitment to E-box in the DBP promoter. In mouse neuro2A cells, melatonin regulates the expression of BMAL1 via PI3K/AKT signaling | Overexpression of ERBB4 enhances the PI3K/AKT pathway conferring oxidative stress protection and inducing rejuvenation of senescent MSC. | Plum et al., 2006; Al-Qassab et al., 2009; Xu et al., 2010; Klockener et al., 2011; Morishita et al., 2016; Saito et al., 2016; Beker et al., 2019; Greenhill, 2019; Liang et al., 2019; Zhou et al., 2020 |
| sensitivity. Hypothalamic JAZF1 regulates hepatic glucose production via the InsR-PI3K-Akt- AMPK pathway and KATP channels. Enhancing PI3K by eliminating PTEN in POMC neurons disrupts leptin-induced KATP channel activity, causing hyperphagia and diet-sensitive obesity. PI3K also contributes to estrogen-mediated energy expenditure in the VMH. | ||||
| REV- ERBa/b | Mice lacking REV-ERBa/b in the SCN display an intrinsic circadian period of 21 hours, leading to a misalignment between internal and external time and resulting in metabolic disruptions | REV-ERBd/β binds to the Rev-Erb/ROR- binding element (RRE), present in the BMAL1 and other CCGs promoters, driving cyclic gene expression | During aging, the circadian oscillation of REV-ERB α and β is reduced, while under caloric restriction (CR), the rhythm of REV–ERB α is recovered. | Aguilar-Arnal and Sassone-Corsi, 2013; Sato et al., 2017; Adlanmerini et al., 2021; Wolffetal., 2023 |
| FOXOs | FOXO1 activates AGRP while inhibiting POMC neurons. | eNAMPT drive circadian rhythms in locomotor activity via NAD+-SIRT- FOXO1-melanocortin pathways. In liver FOXO3 controls Clock expression, therefore, the insulin-FOXO3-Clock axe, modulates hepatic circadian rhythms. | FoxO maintains adult neuronal stem cells reserves and life-long neurogenesis. Induces autophagy genes such as Atg14, Atg4, Atg5, and Atg12. | Kitamura et al., 2006; Chaves et al., 2014; Kim et al., 2015; Park et al., 2023 |
AGRP: Agouti-related protein; AKT: protein kinase B; AMPK: AMP-activated protein kinase; ARC: arcuate nucleus; ATG12: autophagy-related 12; ATG14: autophagy-related 14; ATG4: autophagy-related 4; ATG5: autophagy-related 5; BAT: brown adipose tissue; BMAL1: brain and muscle ARNT-like 1; CCGs: clock-controlled genes; CEBPa: CCAAT/enhancer-binding protein alpha; CLOCK: circadian locomotor output cycles kaput; CR: caloric restriction; CRY1: cryptochrome circadian regulator 1; DBP: D-box binding PAR BZIP transcription factor; Enampt: extracellular nicotinamide phosphoribosyltransferase; ERBB4: Erb-B2 receptor tyrosine kinase 4; FOXO1: forkhead box O1; FOXO3: forkhead box O3; FOXOs: forkhead box O; GSK3B: glycogen synthase kinase 3 beta; HFD: high fat diet; INSR: insulin receptor; JAZF1: JAZF zinc finger 1; JNK: c-Jun N-terminal kinase; KATP: ATP-sensitive potassium channel; LH: lateral hypothalamus; MSC: mesenchymal stem cell; MTOR: mammalian target of rapamycin; NAD: nicotinamide adenine dinucleotide; NSC: neural stem cell; OX2R: orexin 2 receptor; P110B: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta; PER2: period circadian regulator 2; PI3K: phosphoinositide 3-kinase; POMC: pro-opiomelanocortin; PPARG: peroxisome proliferator-activated receptor gamma; PTEN: phosphatase and tensin homolog; PVN: paraventricular nucleus; REV-ERBa: nuclear receptor subfamily 1 group D member 1; REV-ERBb: nuclear receptor subfamily 1 group D member 2; RRE: Rev-Erb/ROR-binding element; S6K1: ribosomal protein S6 kinase 1; SCN: suprachiasmatic nucleus; SF1: steroidogenic factor 1; SIRT1: sirtuin 1; SIRT3: sirtuin 3; SIRT6: sirtuin 6; SIRT7: sirtuin 7; SIRTs: sirtuins; SUCNR1: succinate receptor 1; TGFB1: transforming growth factor beta 1; TSC1: tuberous sclerosis complex 1; TSC2: tuberous sclerosis complex 2; VMH: ventromedial hypothalamus.