The hypothalamus controls food intake [1]. It regulates food intake by integrating information on nutritional status from periphery through nutrients, hormones, and autonomic nervous system. Previous studies revealed that numerous neuropeptides are expressed in the hypothalamus and contribute to the neural networks that regulate food intake. Among them, the melanocortin system—which consists of proopiomelanocortin (POMC), agouti-related peptides (AgRP), and melanocortin receptors—is the most fundamental system regulating food intake. POMC is a precursor for alpha-melanocyte-stimulating hormone (α-MSH), which is an agonist for melanocortin type 4 receptor (MC4R), and AgRP is an inverse agonist for MC4R and counteracts the function of α-MSH. In fact, POMC-null mice [2] and MC4R-null mice [3] are obese, and cases of highly obese humans with MC4R gene mutations have been reported [4–6].

Within the hypothalamus, the arcuate nucleus (ARC), paraventricular nucleus (PVN), and lateral hypothalamic (LH) area are centers for controlling food intake. ARC is the “first-order center” for regulating food intake. It is located at the mediobasal hypothalamus, where the blood–brain barrier is quite permissive, making ARC the place for sensing nutrients and hormone levels. ARC contains two types of neurons: anorexigenic POMC and orexigenic AgRP. These neurons project axons to the “second-order centers,” which are located in PVN and LH, and competitively regulate the activity of these nuclei [7, 8].

The most-studied feeding-related hormone is leptin. In the hypothalamic neurons, leptin activates the Janus kinase 2–signal transducer and activator of transcription 3 (JAK2-STAT3) pathway, leading to nuclear translocation of phosphorylated STAT3. STAT3 suppresses food intake by transactivating the anorexigenic Pomc gene and transrepressing the orexigenic Agrp gene. Insulin is also known as a central regulator for food intake. Neuron-specific insulin receptor knockout mice exhibit increased food intake and obesity [9]. Insulin signaling is transmitted from the insulin receptor to phosphoinositide 3-kinase (PI3K), which subsequently activates a serine/threonine kinase protein kinase B (Akt). FoxO1 is a transcription factor and one of the substrates for Akt. Phosphorylation of FoxO1 by Akt results in cytoplasmic shuttling from the nucleus, thereby inactivating FoxO1 as a transcription factor [10]. FoxO1 is expressed in ARC AgRP and POMC neurons, and FoxO1 in these neurons are located in the nucleus under fasted condition but is shuttled to cytoplasm by feeding [11, 12]. Overexpression of constitutively active FoxO1 in the mediobasal hypothalamus of rats by adenoviral microinjection leads to loss of feeding inhibitory effect of leptin and results in body weight gain [11]. Hypothalamus-specific constitutively active FoxO1 knockin mice also have increased food intake and decreased energy expenditure, and consequently these mice develop obesity [13].

Silent mating type information regulation 2 homolog (sirtuin 1; Sirt1) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase and serves as an energy sensor [14]. Sirt1 is the mammalian ortholog of Sir2, which is crucial for caloric-restriction-induced longevity [15–17]. Sirt1 is expressed in POMC and AgRP neurons in ARC and other hypothalamic nuclei that are important for regulating food intake [18, 19]. There are several reports indicating that Sirt1 affects insulin signaling by modulating the downstream effectors (Fig. 1). For example, Sirt1 deacetylates insulin receptor substrate 2 (IRS2) in hepatocytes, which enhances insulin-induced tyrosine phosphorylation of IRS2 [20]. Sirt1 also decreases transcription of protein tyrosine phosphatase 1B (PTP1B), which results in increased tyrosine phosphorylation of insulin receptor in hepatocytes and myocytes [21]. We also previously reported that Sirt1 deacetylates FoxO1 in pancreatic β cells, enhancing FoxO1 ubiquitination and thereby decreases FoxO1 protein level [22]. Furthermore, Nie et al. [23] reported that Sirt1 deacetylates STAT3, a downstream effector of leptin signaling, and inhibits STAT3 transcriptional activity. If the same mechanism for Sirt1 regulation of insulin and leptin signaling exists in the hypothalamus, Sirt1 should also play an important role in the central regulation of food intake. Therefore, we and others investigated the role of hypothalamic Sirt1 in regulating food intake.

Fig. 1
figure 1

Hormones, nutrients, and neuropeptides controlling food intake. Insulin and leptin control food intake via regulating neuropeptides in the hypothalamus. Nutrients, such as glucose, amino acids, and fatty acids, regulate feeding. Nutrient-sensing proteins, such as adenosine-monophosphate-dependent protein kinase (AMPK), mammalian target of rapamycin (mTOR), and silent mating type information regulation 2 homolog (sirtuin 1; Sirt1) also participate in controlling food intake. Cross-talk among these molecules implicates more complex mechanisms for food intake control

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There is conflicting information on how feeding regulates hypothalamic Sirt1 protein. We found that Sirt1 protein level decreases with fasting in the hypothalamus but not in the cerebral cortex [18]. This hypothalamic Sirt1 response to food intake is lost in diet-induced obese mice. Furthermore, Sirt1 is ubiquitinated in the hypothalamic cells in vitro and in vivo, and fasting increases hypothalamic Sirt1 ubiquitination [18]. On the other hand, Satoh et al. found that dietary restriction increases Sirt1 protein level in the dorsomedial hypothalamus (DMH) and LH [24]. Ramadori et al. [19], found that fasting increased the Sirt1 protein level strictly in the hypothalamus within the brain, which is contrary to our finding.

There are also varying reports on physiological effects of hypothalamic Sirt1 on food intake. In our observation, Sirt1 suppressed hyperphagia and body weight gain induced by overexpression of constitutively active FoxO1 in the mediobasal hypothalamus by adenovirus microinjection, but the effect of hypothalamic Sirt1 overexpression on food intake was not observed in normophagic mice [18]. Satoh et al. [24], observed no change in food intake in their brain-specific Sirt1 transgenic mice, but these mice showed increased physical activity. Intracerebroventricular injection of Sirt1 inhibitor (Ex-527) suppressed food intake [25, 26]. Furthermore, AgRP neuron-specific Sirt1-knockout mice have decreased electric responses of AgRP neurons to ghrelin and decreased food intake [26]. Meanwhile, POMC neuron-specific Sirt1 knockout mice exhibit unchanged food intake, but these mice are hypersensitive to diet-induced obesity due to reduced energy expenditure [27]. We also observed that POMC neuron-specific Sirt1 knockin mice have increased energy expenditure and decreased body weight gain (authors’ unpublished data).

Further investigation is required to clarify the role of hypothalamic Sirt1 in regulating food intake and energy balance. Sirt1 is expressed in most neurons, and it is quite possible that Sirt1 in the different parts of the brain contributes differently to food intake control. Therefore, manipulation of Sirt1 specifically in certain types of neurons or nuclei is important. Interestingly, Sirt1 expression level decreases with age only in ARC but not in DMH, PVN, or ventromedial hypothalamus (VMH) [28]. Aging and high-fat diet reduces Sirt1 expression and activity in a number of tissues [29, 30]. It is possible that the age-dependent loss of Sirt1 in ARC contributes to increased obesity with age, and obesity further accelerates the loss of Sirt1 function in ARC, causing dysregulation of energy balance. The pharmacological activation of Sirt1 confers life span extension in mice fed a high-fat diet [31, 32], but overexpression of Sirt1 in transgenic mice fed a normal diet does not extend life span [33]. These data implicate that Sirt1 promotes health and life of mammals under excessive nutrient conditions but not in normal conditions.

Hypothalamic control of food intake is regulated not only by hormones, such as insulin and leptin, but also by nutrients, such as glucose, amino acids, and FAs. The molecular mechanisms by which these factors control food intake have been uncovered in the past 10 years. Amino acids activate mammalian target of rapamycin (mTOR) signaling in the hypothalamus and suppress food intake [34]. AMP kinase, which also serves as an energy sensor for cells, stimulates food intake [35]. Cross-talk among adenosine-monophosphate-dependent protein kinase (AMPK), mTOR, FoxO1, and Sirt1 have been reported in different experimental systems [36–39], and it is quite possible some of these signaling cross-talks may be functional in the hypothalamus (Fig. 1). We hope that clarifying the molecular mechanism of Sirt1 in controlling food intake will contribute to the development of a new strategy to treat obesity and metabolic syndrome.