Carlos Dieguez

Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance

Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone–induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis.

Adipokines as emerging mediators of immune response and inflammation

The scientific interest in the biology of white adipose tissue (WAT) has increased since the discovery of leptin in 1994. The description of the product of the gene obese (ob) demonstrated the role of adipose tissue in the physiopathology of obesity-related diseases, and helped to increase the identification of numerous other adipokines, many of a pro-inflammatory nature. It has become increasingly evident that WAT-derived adipokines can be considered as a hub between obesity-related exogenous factors, such as nutrition and lifestyle, and the molecular events that lead to metabolic syndrome, inflammatory and/or autoimmune conditions, and rheumatic diseases. In this Review, we will discuss the progress in adipokine research, focusing particular attention to the roles of leptin, adiponectin, resistin, visfatin, and other recently identified adipokines in inflammatory, autoimmune and rheumatic diseases.

Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54

The awakening of the gonadotrophic axis at puberty is the end‐point of a complex cascade of sex developmental events that leads to the attainment of reproductive capacity. Recently, loss‐of‐function mutations of the gene encoding GPR54, the putative receptor for the KiSS‐1‐derived peptide metastin, have been linked to hypogonadotrophic hypogonadism, both in rodents and humans. However, the actual role of the KiSS‐1/GPR54 system in the timing of puberty onset remains unexplored. We report herein that chronic central administration of KiSS‐1 peptide to immature female rats induced the precocious activation of the gonadotrophic axis, as estimated by advanced vaginal opening, elevated uterus weight, and increased serum levels of luteinizing hormone (LH) and oestrogen. The central effect of KiSS‐1 upon LH release appeared to be mediated via the hypothalamic LH‐releasing hormone. In contrast, despite the well‐documented permissive role of body fat stores and the adipocyte‐derived hormone leptin in puberty maturation, acute activation of the gonadotrophic axis by KiSS‐1 was persistently observed in pubertal animals under food deprivation, after central immunoneutralization of leptin, and in a model of leptin resistance. Overall, the present results, together with our recent data on maximum expression of KiSS‐1 and GPR54 genes in the hypothalamus at puberty, provide novel evidence for a role of the KiSS‐1 system as a downstream element in the hypothalamic network triggering the onset of puberty.

Ghrelin, A Novel Placental-Derived Hormone1

Ghrelin, a GH-releasing acylated peptide, has been recently identified from the rat stomach. The purified peptide consists of 28 amino acids in which the serine 3 residue is n-octanoylated. Here we show that ghrelin messenger RNA and ghrelin peptide are present in the human as well as in rat placentae. In human placenta, ghrelin was detected by PCR at both first trimester and after delivery. While ghrelin was not detected by immunohistochemistry in human placenta at term, it was easily identified by immunohistochemistry at first trimester being mainly expressed in cytotrophoblast cells and scarcely in syncytiotrophoblast ones. Ghrelin was also identified in a human choriocarcinoma cell line, the BeWo cells. Ghrelin was found, by immunohistochemistry, in the cytoplasm of labyrinth trophoblast of rat placenta, whereas other placental cell types seems to be negative for ghrelin immunostaining. Moreover, placental ghrelin messenger RNA, in pregnant rats, showed a characteristic profile of expression being practically undetectable during early pregnancy, with a sharp peak of expression at day 16 and decreasing in the latest stages of gestation. In conclusion, ghrelin has been detected in human and rat placenta showing a pregnancy-related time course of expression. Whether placenta-derived ghrelin is involved in the modulation of GH release, or placental cell growth and differentiation remains to be established.

Preliminary evidence that Ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans

An endogenous ligand for the GH secretagogue-receptor (GHS-R) has been recently purified from rat and human stomach and named Ghrelin. It has been demonstrated that Ghrelin specifically stimulates GH secretion from rat pituitary cells in culture as well as in rats in vivo. In this preliminary study, in 4 normal adults [age (mean±SE): 28.6±3.5 yr; body mass index (BMI): 22.3±2.1 kg/m2] we administered 1.0 μg/kg Ghrelin or GHRH-29 to compare their GH-releasing activities in humans. In all subjects Ghrelin induced a prompt, marked and long-lasting increase in circulating GH levels (peak: 107.9±26.1 μg/l; AUC: 6503.1±1632.7 μg/l/h). The GH response to Ghrelin was clearly higher (p<0.05) than that after GHRH (peak: 22.3±4.5 μg/l; AUC: 1517.5±338.4 μg/l/h). In conclusion, this preliminary study shows that Ghrelin exerts a strong stimulatory effect on GH secretion in humans releasing more GH than GHRH.

Hypothalamic Fatty Acid Metabolism Mediates the Orexigenic Action of Ghrelin

Current evidence suggests that hypothalamic fatty acid metabolism may play a role in regulating food intake; however, confirmation that it is a physiologically relevant regulatory system of feeding is still incomplete. Here, we use pharmacological and genetic approaches to demonstrate that the physiological orexigenic response to ghrelin involves specific inhibition of fatty acid biosynthesis induced by AMP-activated protein kinase (AMPK) resulting in decreased hypothalamic levels of malonyl-CoA and increased carnitine palmitoyltransferase 1 (CPT1) activity. In addition, we also demonstrate that fasting downregulates fatty acid synthase (FAS) in a region-specific manner and that this effect is mediated by an AMPK and ghrelin-dependent mechanisms. Thus, decreasing AMPK activity in the ventromedial nucleus of the hypothalamus (VMH) is sufficient to inhibit ghrelins effects on FAS expression and feeding. Overall, our results indicate that modulation of hypothalamic fatty acid metabolism specifically in the VMH in response to ghrelin is a physiological mechanism that controls feeding.

Neuroendocrine Regulation and Actions of Leptin

The discovery of the adipocyte-produced hormone leptin has greatly changed the field of obesity research and our understanding of energy homeostasis. It is now accepted that leptin is the afferent loop informing the hypothalamus about the state of fat stores, with hypothalamic efferents regulating appetite and energy expenditure. In addition, leptin has a role as a metabolic adaptator in overweight and fasting states. New and previously unsuspected neuroendocrine roles have emerged for leptin. In reproduction, leptin is implicated in fertility regulation, and it is a permissive factor for puberty. Relevant gender-based differences in leptin levels exist, with higher levels in women at birth, which persist throughout life. In adult life, there is experimental evidence that leptin is a permissive factor for the ovarian cycle, with a regulatory role exerted at the hypothalamic, pituitary, and gonadal levels, and with unexplained changes in pregnancy and postpartum. Leptin is present in human milk and may play a role in the adaptive responses of the newborn. Leptin plays a role in the neuroendocrine control of GH secretion, through a complex interaction at hypothalamic levels with GHRH and somatostatin. Leptin participates in the expression of CRH in the hypothalamus, interacts at the adrenal level with ACTH, and is regulated by glucocorticoids. Since leptin and cortisol show an inverse circadian rhythm, it has been suggested that a regulatory feedback is present. Finally, regulatory actions on TRH-TSH and PRL secretion have been found. Thus leptin reports the state of fat stores to the hypothalamus and other neuroendocrine areas, and the neuroendocrine systems adapt their function to the current status of energy homeostasis and fat stores.

AMPK: a metabolic gauge regulating whole-body energy homeostasis

AMP-activated protein kinase (AMPK) is the downstream component of a kinase cascade that acts as a gauge of cellular energy levels. Over the last few years, accumulating evidence has demonstrated that AMPK is also involved in the regulation of energy balance at the whole-body level by responding to hormones and nutrient signals, which leads to changes in energy homeostasis. The physiological relevance of this new role of AMPK is demonstrated by the fact that impairment of AMPK function is associated with metabolic alterations, insulin resistance, obesity, hormonal disorders and cardiovascular disease. Here, we summarize the role of AMPK in the regulation of energy homeostasis. Understanding this key enzyme and its tissue-specific regulation will provide new targets for the treatment of metabolic disorders.

Leptin, from fat to inflammation: old questions and new insights

Leptin is 16 kDa adipokine that links nutritional status with neuroendocrine and immune functions. Initially thought to be a satiety factor that regulates body weight by inhibiting food intake and stimulating energy expenditure, leptin is a pleiotropic hormone whose multiple effects include regulation of endocrine function, reproduction, and immunity. Leptin can be considered as a pro‐inflammatory cytokine that belongs to the family of long‐chain helical cytokines and has structural similarity with interleukin‐6, prolactin, growth hormone, IL‐12, IL‐15, granulocyte colony‐stimulating factor and oncostatin M. Because of its dual nature as a hormone and cytokine, leptin links the neuroendocrine and the immune system. The role of leptin in the modulation of immune response and inflammation has recently become increasingly evident. The increase in leptin production that occurs during infection and inflammation strongly suggests that leptin is a part of the cytokine network which governs the inflammatory‐immune response and the host defense mechanisms. Leptin plays an important role in inflammatory processes involving T cells and has been reported to modulate T‐helper cells activity in the cellular immune response. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions, such as experimental autoimmune encephalomyelitis, type 1 diabetes, rheumatoid arthritis, and intestinal inflammation. Very recently, a key role for leptin in osteoarthritis has been demonstrated: leptin indeed exhibits, in concert with other pro‐inflammatory cytokines, a detrimental effect on articular cartilage by promoting nitric oxide synthesis in chondrocytes. Here, we review the recent advances regarding leptin biology with a special focus on those actions relevant to the role of leptin in the pathophysiology of inflammatory processes and immune responses.

Regulation of in Vivo Growth Hormone Secretion by Leptin

Leptin, the product of the ob gene, is a recently discovered hormone secreted by adipocytes that regulates food intake and energy expenditure. Growth hormone (GH) secretion is markedly influenced by body weight being markedly suppressed in obesity and underweight. The aim of the present study was to study whether leptin can act as a metabolic signal connecting the adipose tissue with the growth hormone axis. We administered leptin antiserum (10 ul, i.c.v.) or normal rabbit serum (NRS; 10 ul, i.c.v.) to freely moving fed rats. Furthermore we assessed the effect of leptin administration (10 ug, i.c.v.) on fed and fasted rats. Spontaneous GH secretion was assessed over 6 hours with blood samples taken every 15 min. Administration of leptin antiserum led to a decrease in spontaneous GH secretion as assessed by the area under the curve (AUC) (168 ± 72 ng/ml/6h) in comparison to NRS-treated rats (813 ± 179 ng/ml/6 h, p < 0.01). While leptin administration (10 ug/rat; i.c.v.) to normal fed rats did not modify sp...