Scope
Dysbiosis of gut microbiota is involved in metabolic syndrome (MetS) development, which has a different incidence between men (M) and women (W). The differences in gut microbiota in MetS ...patients are explored according to gender, and whether consuming two healthy diets, Mediterranean (MED) and low‐fat (LF), may, over time, differentially shape the gut microbiota dysbiosis according to gender is evaluated.
Materials and Methods
All the women from the CORDIOPREV study whose feces samples were available and a similar number of men, matched by the main metabolic variables (N = 246, 123 women and 123 men), and categorized according to the presence or not of MetS are included. Gut microbiota is analyzed at baseline and after 3 years of dietary intervention.
Results
Higher abundance of Collinsella, Alistipes, Anaerotruncus, and Phascolarctobacterium genera is observed in MetS‐W than in MetS‐M, whereas the abundance of Faecalibacterium and Prevotella genera is higher in MetS‐M than in MetS‐W. Moreover, higher levels of Desulfovibrio, Roseburia, and Holdemania are observed in men than in women after the consumption of the LF diet.
Conclusion
The results suggest the potential involvement of differences in gut microbiota in the unequal incidence of metabolic diseases between genders, and a sex‐dependent effect on shaping the gut microbiota according to diet.
Dysbiosis of gut microbiota is involved in the development of metabolic syndrome, whose incidence is different between men and women. This work provides evidence of a different gut microbiota composition in metabolic syndrome, according to gender. Moreover, the study shows a differential shaping of the gut microbiota according to the gender in metabolic syndrome patients after the consumption of a Mediterranean or a low‐fat diet for three years.
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among reproductive age women. Although its cardinal manifestations include hyperandrogenism, oligo/anovulation, and/or polycystic ...ovarian morphology, PCOS women often display also notable metabolic comorbidities. An array of pathogenic mechanisms have been implicated in the etiology of this heterogeneous endocrine disorder; hyperandrogenism at various developmental periods is proposed as a major driver of the metabolic and reproductive perturbations associated with PCOS. However, the current understanding of the pathophysiology of PCOS-associated metabolic disease is incomplete, and therapeutic strategies used to manage this syndrome's metabolic complications remain limited.
This study is a systematic review of the potential etiopathogenic mechanisms of metabolic dysfunction frequently associated with PCOS, with special emphasis on the metabolic impact of androgen excess on different metabolic tissues and the brain. We also briefly summarize the therapeutic approaches currently available to manage metabolic perturbations linked to PCOS, highlighting current weaknesses and future directions.
Androgen excess plays a prominent role in the development of metabolic disturbances associated with PCOS, with a discernible impact on key peripheral metabolic tissues, including the adipose, liver, pancreas, and muscle, and very prominently the brain, contributing to the constellation of metabolic complications of PCOS, from obesity to insulin resistance. However, the current understanding of the pathogenic roles of hyperandrogenism in metabolic dysfunction of PCOS and the underlying mechanisms remain largely incomplete. In addition, the development of more efficient, even personalized therapeutic strategies for the metabolic management of PCOS patients persists as an unmet need that will certainly benefit from a better comprehension of the molecular basis of this heterogeneous syndrome.
Procreation is essential for survival of species. Not surprisingly, complex neuronal networks have evolved to mediate the diverse internal and external environmental inputs that regulate reproduction ...in vertebrates. Ultimately, these regulatory factors impinge, directly or indirectly, on a final common pathway, the neurons producing the gonadotropin-releasing hormone (GnRH), which stimulates pituitary gonadotropin secretion and thereby gonadal function. Compelling evidence, accumulated in the last few years, has revealed that kisspeptins, a family of neuropeptides encoded by the Kiss1 gene and produced mainly by neuronal clusters at discrete hypothalamic nuclei, are pivotal upstream regulators of GnRH neurons. As such, kisspeptins have emerged as important gatekeepers of key aspects of reproductive maturation and function, from sexual differentiation of the brain and puberty onset to adult regulation of gonadotropin secretion and the metabolic control of fertility. This review aims to provide a comprehensive account of the state-of-the-art in the field of kisspeptin physiology by covering in-depth the consensus knowledge on the major molecular features, biological effects, and mechanisms of action of kisspeptins in mammals and, to a lesser extent, in nonmammalian vertebrates. This review will also address unsolved and contentious issues to set the scene for future research challenges in the area. By doing so, we aim to endow the reader with a critical and updated view of the physiological roles and potential translational relevance of kisspeptins in the integral control of reproductive function.
Puberty is a crucial biological process normally occurring at a specific time during the lifespan, during which sexual and somatic maturation are completed, and reproductive capacity is reached. ...Pubertal timing is not only determined by genetics, but also by endogenous and environmental cues, including nutritional and metabolic signals. During the last decade, we have learned much regarding the essential roles of kisspeptins and the neuropeptide pathways that converge on these neurones to modulate kisspeptin signalling, as well as neurokinin B and dynorphin, the co‐transmitters of Kiss1 neurones in the arcuate nucleus, and the effects of melanocortins on puberty. Indeed, melanocortins are involved in transmitting the regulatory actions of metabolic cues on pubertal maturation. Intracellular metabolic sensors, such as the AMP‐activated protein kinase and the fuel‐sensing deacetylase SIRT1, have been shown to contribute to puberty. Further understanding of these signals and regulatory circuits will help uncover the intimacies of the central control of puberty, as well as how alterations in metabolic status, ranging from undernutrition to obesity, affect the pubertal process. Precocious puberty is rare and has a clear female predominance. Central precocious puberty (CPP) is diagnosed when premature activation of the hypothalamic‐pituitary axis occurs. Its causes are heterogeneous, with alterations of the central nervous system being of special interest, and with environmental factors also playing a role in some cases. During the last decade, several mutations in different genes (including KISS1, KISS1R, MKRN3 and DLK1) that cause CPP have been discovered. Loss‐of‐function mutations in MKRN3 are the most common monogenic cause of CPP known to date. Here, we review and update what is known regarding the genotype‐phenotype relationship in patients with CPP.
Pubertal onset is controlled by neurones of the hypothalamus. These neurones also detect energy excess and energy deficiency, which can impact the timing of puberty.
Highlights • Estrogens are pleiotropic regulators affecting not only reproduction but also metabolism. • Estrogen deprivation induces hyperphagia, low metabolic activity, and obesity. • Estrogen ...actions are conducted via genomic and nongenomic mechanisms, including ERα. • Estrogens act in the brain to regulate all aspects of body energy homeostasis and metabolism. • Estrogen actions in the ARC regulate food intake and in the VMH energy expenditure.
The kisspeptin receptor, Kiss1R, also known as Gpr54, is a G protein-coupled receptor (GPCR), deorphanized in 2001, when it was recognized as canonical receptor for the Kiss1-derived peptides, ...kisspeptins. In 2003, inactivating mutations of Kiss1R gene were first associated to lack of pubertal maturation and hypogonadotropic hypogonadism in humans and rodents. These seminal findings pointed out the previously unsuspected, essential role of Kiss1R and its ligands in control of reproductive maturation and function. This contention has been fully substantiated during the last decade by a wealth of clinical and experimental data, which has documented a fundamental function of the so-called Kiss1/Kiss1R system in the regulation of puberty onset, gonadotropin secretion and ovulation, as well as the metabolic and environmental modulation of fertility. In this review, we provide a succinct summary of some of the most salient facets of Kiss1R, as essential GPCR for the proper maturation and function of the reproductive axis.
Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin‐releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor ...1 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β‐Klotho (KLB), the obligate co‐receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH. Genetic screening of 334 CHH patients identified seven heterozygous loss‐of‐function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction.
Synopsis
Defects in FGF21/KLB/FGFR1 signaling contribute to GnRH deficiency in both humans and mice. This signaling pathway is a novel link between metabolism and reproduction.
Heterozygous loss‐of‐function mutations in KLB are found in patients with congenital hypogonadotropic hypogonadism.
Klb‐deficient mice delayed sexual maturation and impaired fertility with decreased gonadotropins due to a hypothalamic defect.
Klb is expressed in the postnatal hypothalamus including GnRH neurons.
FGF21 reaches GnRH neurons via fenestrated capillaries in the hypothalamus in vivo and enhances GnRH release in median eminence explants in vitro.
Defects in FGF21/KLB/FGFR1 signaling contribute to GnRH deficiency in both humans and mice. This signaling pathway is a novel link between metabolism and reproduction.
This article is part of a Special Issue “Puberty and Adolescence”.
Reproduction is an energy-demanding function. Accordingly, puberty is metabolically gated, as a means to prevent fertility in ...conditions of energy insufficiency. In addition, obesity has been shown to impact the timing of puberty and may be among the causes for the earlier trends of pubertal age reported in various countries. The metabolic control of puberty in such a spectrum of situations, ranging from energy deficit to extreme overweight, is the result of the concerted action of different peripheral hormones and central transmitters that sense the metabolic state of the organism and transmit this information to the various elements of the reproductive axis, mainly the GnRH neurons. Among the peripheral signals involved, the adipose hormone, leptin, is known to play an essential role in the regulation of puberty, especially in females. Yet, although it is clear that the effects of leptin on puberty onset are predominantly permissive and mainly conducted at central (hypothalamic) levels, the primary sites and mechanisms of action of leptin within the reproductive brain remain unsolved. In this context, neurons expressing kisspeptins, the products of the Kiss1 gene that have emerged recently as essential upstream regulators of GnRH neurons, operate as key sensors of the metabolic state and funnel of the reproductive effects of leptin. Yet, much debate has arisen recently on whether the putative actions of leptin on the Kiss1 system are actually indirect and/or may primarily target Kiss1-independent pathways, such as those originating from the ventral premmamilary nucleus. Moreover, evidence has been presented for extra-hypothalamic or peripheral actions of leptin, including direct gonadal effects, which may contribute to the metabolic control of reproduction in extreme body weight conditions. In this work, we will critically review the experimental evidence supporting a role of leptin, kisspeptin and putatively related pathways in the concerted control of puberty by energy balance and metabolism.
► Puberty is metabolically gated; it occurs only if sufficient fuel stores are available. ► Leptin plays a permissive role in puberty, especially in females; threshold levels are needed for puberty to proceed. ► Kiss1 neurons sense and transmit metabolic information to GnRH neurons ► Leptin stimulates Kiss1 neurons likely via indirect actions (mainly). ► Leptin targets also other circuits (e.g. the PMV) that might project to Kiss1 neurons.
Polycystic ovary syndrome (PCOS) is a highly prevalent heterogeneous disease characterized by ovulatory dysfunction, hyperandrogenism, and metabolic alterations. Women with PCOS commonly display ...dysregulated gonadotropin secretion with higher LH pulsatility and perturbed LH-FSH ratios, which likely contributes to the ovarian phenotype and might be indicative of disrupted GnRH secretory activity. Although the involvement of altered androgen and insulin levels in the pathogenesis of the neuroendocrine alterations of PCOS has been explored in various experimental and clinical settings, the ultimate mechanisms whereby such neurohormonal perturbations take place remain partially unknown. In recent years, kisspeptins, the products of the Kiss1 gene that operate via the surface receptor Gpr54, have emerged as essential elements of the reproductive brain that play an indispensable role in the control of gonadotropin secretion and ovulation. In addition, Kiss1 neurons in the brain are targets and transmitters of the regulatory actions of sex steroids and metabolic cues on the reproductive axis during early organizing periods and adulthood. Furthermore, Kiss1/kisspeptin expression has been documented in the ovary in various species, including humans; yet clear evidence for the involvement of kisspeptin signaling in the control of ovulation, or its alterations, is still pending. Based on these physiologic features, we discuss the putative pathophysiologic implications of alterations of the Kiss1 system in the generation of PCOS and summarize the scarce experimental and clinical evidence that might support such a role.
Body energy and metabolic homeostasis are exquisitely controlled by multiple, often overlapping regulatory mechanisms, which permit the tight adjustment between fuel reserves, internal needs, and ...environmental (e.g., nutritional) conditions. As such, this function is sensitive to and closely connected with other relevant bodily systems, including reproduction and gonadal function. The aim of this mini-review article is to summarize the most salient experimental data supporting a role of the amygdala as a key brain region for emotional learning and behavior, including reward processing, in the physiological control of feeding and energy balance. In particular, a major focus will be placed on the putative interplay between reproductive signals and amygdala pathways, as it pertains to the control of metabolism, as complementary, extrahypothalamic circuit for the integral control of energy balance and gonadal function.
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