White adipose tissue is no longer considered an inert tissue mainly devoted to energy storage but is emerging as an active participant in regulating physiologic and pathologic processes, including immunity and inflammation. Macrophages are components of adipose tissue and actively participate in its activities. Furthermore, cross-talk between lymphocytes and adipocytes can lead to immune regulation. Adipose tissue produces and releases a variety of proinflammatory and anti-inflammatory factors, including the adipokines leptin, adiponectin, resistin, and visfatin, as well as cytokines and chemokines, such as TNF-α, IL-6, monocyte chemoattractant protein 1, and others. Proinflammatory molecules produced by adipose tissue have been implicated as active participants in the development of insulin resistance and the increased risk of cardiovascular disease associated with obesity. In contrast, reduced leptin levels might predispose to increased susceptibility to infection caused by reduced T-cell responses in malnourished individuals. Altered adipokine levels have been observed in a variety of inflammatory conditions, although their pathogenic role has not been completely clarified.

https://www.jacionline.org/article/S0091-6749(05)00417-3/pdf

Adipose tissue, adipokines, and inflammation.

Immunometabolism is emerging an important area of immunological research, but for many immunologists the complexity of the field can be daunting. Here, the authors provide an overview of six key metabolic pathways that occur in immune cells and explain what is known (and what is still to be uncovered) concerning their effects on immune cell function. In recent years a substantial number of findings have been made in the area of immunometabolism, by which we mean the changes in intracellular metabolic pathways in immune cells that alter their function. Here, we provide a brief refresher course on six of the major metabolic pathways involved (specifically, glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, fatty acid oxidation, fatty acid synthesis and amino acid metabolism), giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response. What is emerging is a complex interplay between metabolic reprogramming and immunity, which is providing an extra dimension to our understanding of the immune system in health and disease.

A guide to immunometabolism for immunologists

Received June 28, 2004; revision received August 26, 2004; accepted October 15, 2004 

The original description of the metabolic syndrome by Reaven1 consisted of obesity, insulin resistance, hypertension, impaired glucose tolerance or diabetes, hyperinsulinemia and dyslipidemia characterized by elevated triglyceride, and low HDL concentrations All of the features described above are risk factors for atherosclerosis, and thus, metabolic syndrome constituted a significant risk for coronary heart disease2–5 (Table) The features of obesity/overweight and insulin resistance also provided a significant risk for developing type 2 diabetes5,6 The risks for coronary heart disease and diabetes with metabolic syndrome are greater than those for simple obesity alone, and therefore, an understanding of the pathogenesis and through it, a rational approach to its therapy are of prime importance 

View this table:

Classic Biological Effects of Insulin and Classic Metabolic Syndrome Based on Resistance to the Metabolic Effects of Insulin 



As our understanding of the action of insulin evolves to comprehensively include the recent discoveries,7 we can better see that insulin resistance is the basis of most if not all of the features of this syndrome The original conceptualization of this syndrome was on the basis of resistance to the metabolic actions of insulin Thus, hyperinsulinemia, glucose intolerance, type 2 diabetes, hypertriglyceridemia, and low HDL concentrations could be accounted for by resistance to the actions of insulin on carbohydrate and lipid metabolism Although the features described above would to some extent explain the atherogenesis, Reaven has maintained that hyperinsulinemia itself contributes to atherogenicity, and thus, insulin is atherogenic, leading to the coronary heart disease and cerebrovascular disease associated with this syndrome

Obesity probably leads to hypertension through (1) increased vascular tone created by a reduced bioavailability of NO because of increased oxidative stress,8 (2) increased asymmetric dimethylarginine (ADMA) concentrations,9 (3) increased sympathetic …

Metabolic Syndrome A Comprehensive Perspective Based on Interactions Between Obesity, Diabetes, and Inflammation

Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. As a hormone, leptin regulates food intake and basal metabolism, and is sexually dimorphic — that is, its serum concentration is higher in females than in males with a similar body fat mass. As a cytokine, leptin can affect thymic homeostasis and the secretion of acute-phase reactants such as interleukin-1 and tumour-necrosis factor. Similar to other pro-inflammatory cytokines, leptin promotes T helper 1 (TH1)-cell differentiation and can modulate the onset and progression of autoimmune responses in several animal models of disease. Here, we review the advances and controversy for a role of leptin in the pathophysiology of immune responses.

The weight of leptin in immunity

Leptin is a versatile 16 kDa peptide hormone, with a tertiary structure resembling that of members of the long-chain helical cytokine family. It is mainly produced by adipocytes in proportion to fat size stores, and was originally thought to act only as a satiety factor. However, the ubiquitous distribution of OB-R leptin receptors in almost all tissues underlies the pleiotropism of leptin. OB-Rs belong to the class I cytokine receptor family, which is known to act through JAKs (Janus kinases) and STATs (signal transducers and activators of transcription). The OB-R gene is alternatively spliced to produce at least five isoforms. The full-length isoform, OB-Rb, contains intracellular motifs required for activation of the JAK/STAT signal transduction pathway, and is considered to be the functional receptor. Considerable evidence for systemic effects of leptin on body mass control, reproduction, angiogenesis, immunity, wound healing, bone remodelling and cardiovascular function, as well as on specific metabolic pathways, indicates that leptin operates both directly and indirectly to orchestrate complex pathophysiological processes. Consistent with leptin's pleiotropic role, its participation in and crosstalk with some of the main signalling pathways, including those involving insulin receptor substrates, phosphoinositide 3-kinase, protein kinase B, protein kinase C, extracellular-signal-regulated kinase, mitogen-activated protein kinases, phosphodiesterase, phospholipase C and nitric oxide, has been observed. The impact of leptin on several equally relevant signalling pathways extends also to Rho family GTPases in relation to the actin cytoskeleton, production of reactive oxygen species, stimulation of prostaglandins, binding to diacylglycerol kinase and catecholamine secretion, among others.

/pdf/intracellular-signalling-pathways-activated-by-leptin-5g2dpqprhe.pdf

Intracellular signalling pathways activated by leptin

In all the studies, normogonadotropic patients Lutropin Alfa were given once-daily r-hLH 75–150 IU. These A Viewpoint by Giuseppe De Placido, doses were established based on trials performed in Roberto Clarizia and Carlo Alviggi women with hypogonadotropic hypogonadism and Department of Obstetrics, Gynecology, Urology in which mono-ovulation represented the clinical and Reproductive Medicine, Federico II target. Recombinant LH is characterized by a short University of Naples, Naples, Italy half-life (1.9 h) and, unlike hCG, mediates a rapid and transient message. It is not possible to exclude the possibility that during multiple follicular growth, Recombinant-DNA technology has provided us a higher and more persistent LH stimulus may be with qualitatively and quantitatively consistent required. preparations of gonadotropins. Thus, we can treat patients separately with recombinant human follicle In conclusion, there appears to be no doubt about stimulating hormone (r-hFSH) and recombinant the usefulness of r-hLH in hypogonadotropic hyhuman luteinizing hormone (r-hLH) according to pogonadal women. Although initial data from northe specific indication. Hypogonadotropic hymogonadotropic women undergoing IVF are enpogonadism is the main indication where r-hLH is couraging, there is a lack of adequately sized studies used along with r-hFSH. This clinical approach is evaluating implantation and pregnancy rates as priconsistent with the classical ‘two cell–two gonadomary endpoints. Moreover, higher dosages of r-hLH tropins’ theory. should be tested in these patients. ▲

Lutropin alfa: a viewpoint by Giuseppe De Placido, Roberto Clarizia and Carlo Alviggi.

Double stimulation in a single menstrual cycle increases the number of oocytes retrieved in poor prognosis patients undergoing IVF treatment. Prospective study with historical control

Ovarian reserve tests: Are they only a quantitative measure?

UNLABELLED Deficiency of 17β-hydroxysteroid dehydrogenase type 3 (17βHSD3), an enzyme converting androstenedione (A) to testosterone (T), is a rare cause of autosomal recessive 46,XY disorder of sexual development (DSD). A 18-years phenotypically female patient from southern Italy presented with primary amenorrhea. She had deep voice, macrocephaly, enlarged and bulbous nasal tip, macrostomia, facial acne, breast asymmetry, hypoplasia of the first finger of right hand, proximal implant of the fifth metatarsus bilaterally as well as an increased muscle mass and hirsutism, with hair distribution on face, neck, chest, abdomen, pubic region and on upper and lower limbs. Genital exam showed thickened labra majora with absence of labra minora and a blind-ending pseudo-vagina with clitoris enlargement. Karyotype analysis showed a male genotype (46,XY). Hormonal evaluation showed decreased T (188 ng/dL-6.5 nmol/L) and increased A (10 ng/mL-34,96 nmol/L), considering male reference ranges, resulting in a decreased T/A ratio (0,186). MRI identified testicles in inguinal regions. Human Chorionic Gonadotropin test showed T/A ratio permanently under 0,8. These evidences were suggestive of a 46,XY DSD due to 17βHSD3 deficiency. An homozygous mutation (IVS3 -1 G>C or c.326-1G>C) of the 17βHSD3 gene was discovered. Psychologist identified a well determined female gender identity. It was decided to proceed with gonadectomy and vaginal enlargement by use of dilatators. CONCLUSION The case described represents a new case of DSD due to 17βHSD3 deficiency. This patient, raised as a girl, is diagnosed in a very late stage. The identified mutation, previously reported only in Dutch and Brazilian population, is one of 27 presently known mutations of 17βHSD3 gene and is never reported in Italian population.

The 17β-hydroxysteroid dehydrogenase type 3 deficiency: a case report of an 18-year patient and review of the literature.

Carlo Alviggi

Papers

Lutropin alfa: a viewpoint by Giuseppe De Placido, Roberto Clarizia and Carlo Alviggi.

Double stimulation in a single menstrual cycle increases the number of oocytes retrieved in poor prognosis patients undergoing IVF treatment. Prospective study with historical control

Ovarian reserve tests: Are they only a quantitative measure?

The 17β-hydroxysteroid dehydrogenase type 3 deficiency: a case report of an 18-year patient and review of the literature.

Unexpected ovarian activity in premenopausal breast cancer survivors treated with exemestane and GnRH analogues