4. SIRT1 Functions in the Hypothalamic-Pituitary-Gonadal (HPG) Axis
The HPG axis plays a significant role in regulating reproductive functions, life cycle, and sexual dimorphism. SIRT1 is a key player in regulating the activities of the HPG (hypothalamus-pituitary–gonadal) axis and neuroendocrine systems[
73].
Sirt1 is expressed in neurons as well, particularly those that control the hypothalamus’ metabolic activity [
73]. There exists a diffused network of GnRH neurons called pulse-generator in the hypothalamus; it is responsible for the releasing of GnRH. Gonads synthesize estrogen and testosterone under the influence of LH and FSH secreted under the stimulation of pulsatile secretion of GnRH[
74,
75].
Sirt1-knockout results in decreased hypothalamic gonadotropin-releasing hormone (GnRH) expression, and consequently lower serum LH and FSH levels and aberrant spermatogenesis, suggesting the significance of SIRT1 in regulating the HPG axis[
42]. Furthermore,
miR-132/212-mediated action of GnRH involved a posttranscriptional decrease in
Sirt1. Subsequently, SIRT1-dependent FOXO1 deacetylation was decreased, limiting FOXO1-mediated inhibition of Fshβ transcription. This decrease in the FOXO1 deacetylation resulted in upregulation of Fshβ in rat primary pituitary cells and LβT2 cell line [
76], further supporting the significance of SIRT1 in the HPG axis.
The function of SIRT1 has also been discovered in the hypothalamic Kiss1 neurons, where it inhibits
Kiss1 activity [
77]. Hence, SIRT1 controls puberty by regulating the puberty-stimulating gene,
Kiss1 [
77]. In line with it,
Sirt1-deficient mice exhibited central hypogonadism due to aberrant migration of GnRH neurons to the hypothalamus, suggesting that SIRT1 may play an important role in the regulation of the reproductive axis [
78]. In addition, hypogonadotropic hypogonadism has been found in
Sirt1−/− mice due to failure of GnRH neural migration. SIRT1’s catalytic domain promotes GN11 (mouse neuronal cell line) migration via deacetylating cortactin [
78]. SIRT1 is found in the steroidogenic factor 1 (SF1) neuron of the ventromedial hypothalamic nucleus (VMH) and the pro-opiomelanocortin (POMC) and agouti-related protein (AgRP) neurons of the arcuate nucleus (ARH) [
79,
80,
81]. Due to aberrant sympathetic activity, energy imbalance was seen in POMC neuron-specific
Sirt1−/− mice [
80]. Likewise, insulin resistance in skeletal muscles was observed in
Sirt1-deficient SF1 neurons, while
Sirt1-overexpression resulted in induced obesity and insulin resistance [
79]. Moreover, overexpression of
Sirt1 prevented age-related weight gain in POMC or AgRP neurons. However, energy expenditure due to sympathetic activity was increased in the former one while food intake was reduced in the latter one, suggesting the existence of a hypothalamic nuclei-specific regulation [
81]. Moreover, there was a higher level of SIRT1 in dorsomedial (DMH) and lateral hypothalamic nuclei (LHN) upon limiting the food provision [
8]. Overexpression of
Sirt1 in the brain cells of mice resulted in a longer life span characterized by the overactivity of DMH and LHN via elevated levels of orexin type 2 receptor (Ox2r) [
8], suggesting a tissue-specific role of SIRT1 in regulating and maintaining hunger, use of energy, metabolic activities, and longevity.
Sirt1-knockdown results in low testosterone biosynthesis as it affects the Leydig cell maturation and reduces the steroidogenic acute regulatory protein (StAR) level [
42]. Our group has recently reported that
Sirt1-deficiency in the Leydig cells interferes with the cholesterol uptake due to compromised autophagy, and consequently results in a decreased testosterone biosynthesis in mice [
82]. A steroidogenic cell-specific
Sirt1-knockout mouse line was generated via mating
Sirt1F/F mice with
SF1-Cre strain. We found a significant decrease in testosterone levels and mating efficiency in
Sirt1−/− mice. However, we found no differences in the testis size upon
Sirt1-deletion. Furthermore, we observed that the mating efficiency instead of spermatogenesis was compromised in these mice[
65,
82]. Finally, we figured out that, upon SIRT1-mediated deacetylation, LC3 moves from the nucleus to the cytoplasm and helps autophagosome formation, which degrades the NHERF2 (a negative regulator of cholesterol uptake receptor, scavenger receptor class B type I (SR-BI)). Consequently, it maintains the SR-BI level to uptake cholesterol, thus fueling the process of steroidogenesis. However, in
Sirt1−/− mice, LC3 remains in the nucleus, inhibiting NHERF2 clearance, thus stopping SR-BI expression and cholesterol uptake, finally resulting in reduced testosterone biosynthesis.
Proinflammatory cytokines also have an important role in steroidogenesis [
83]. SIRT1 has significant anti-inflammatory effects in the presence of cytokines [
84].
Sirt1 gene and protein levels in TNF-α-treated TM3 cells were found to be considerably lower, as were testicular
Sirt1 mRNA levels in high-fat-induced obese mice. A huge increase in the cytokines and decrease in the genes expression of several steroidogenic enzymes were observed in
Sirt1-deficient TM3 cells. This boom in cytokine levels halts the transactivation of
SF1. In contrast,
Sirt1-overexpression enhances
SF1-activity and consequently the steroidogenic enzymes and testosterone biosynthesis [
84].