Leptin: Mechanisms Involved In Signaling and Resistance

Leptin is secreted mainly by white adipocyte tissue, and it circulates at levels positively correlated with fat mass, thus reflecting primarily the amount of energy stored in adipose tissue. Leptin levels also change with acute changes in energy intake and thus, secondarily reflect acute energy availability. Several potential mechanisms behind leptin resistance have been identified including: Inflammatory signaling, elevated free fatty acids, high leptin and genetic mutation in OB and DBU genes. This review summaries all the physiological, biological aspects of leptin hormone including increases energy expenditure, thermogenesis, heart rate, blood pressure but decreases glycaemia. This review summarizes the pharmacological and nonpharmacological treatment of leptin hormone imbalances.

The relation between obesity, kisspeptin, leptin, and male fertility

Over the past decades, obesity and infertility in men increased in parallel, and the association between both phenomena have been examined by several researchers. despite the fact that there is no agreement, obesity appears to affect the reproductive potential of men through various mechanisms, such as changes in the hypothalamic-pituitary-testicular (HPT) axis, spermatogenesis, sperm quality and/or alteration of sexual health. Leptin is a hormone produced by the adipose tissue, and its production elevates with increasing body fat. Many studies have supported the relationship between raised leptin production and reproductive function regulation. In fact, Leptin acts on the HPT axis in men at all levels. However, most obese men are insensitive to increased production of endogenous leptin and functional leptin resistance development. Recently, it has been recommended that Kisspeptin neurons mediate the leptin’s effects on the reproductive system. Kisspeptin binding to its receptor on gonadotropin-releasing hormone (GnRH) neurons, activates the mammal’s reproductive axis and stimulates GnRH release. Increasing infertility associated with obesity is probably mediated by the Kisspeptin-GnRH pathway. In this review, the link between obesity, kisspeptin, leptin, and male fertility will be discussed.

CHARACTERISTICS OF METABOLIC PROCESSES IN THE FORMATION OF MENSTRUAL FUNCTION DISORDERS IN ADOLESCENT GIRLS WITH OBESITY

Іntroduction. Today, a quarter of the population of economically developed countries has a body weight that is 15% larger than the norm. According to various authors, the timely onset of menarche in women with various forms of obesity and reproductive dysfunction is observed in 31% of cases only. Obesity results in insulin resistance, which in its turn results in hyperinsulinemia. The main reason of the connection of insulin resistance with reproductive function disorders consists in the specific influence of insulin on ovaries. Insulin suppresses apoptosis, binding to receptors of various growth factors that promotes long existence of atresizing follicles. In the pathogenesis of the metabolic syndrome, along with the development of hyperinsulinemia and insulin resistance, a significant role belongs to the imbalance of adipocytokines, one of which is adiponectin. The aim is to analyze metabolic processes in the formation of menstrual dysfunction in adolescent girls with obesity to improve diagnostic methods of menstrual disorders. Material and methods. Clinical and laboratory examination of adolescent girls aged 12-18 years was held, among which 79 had obesity and complaints about menstrual dysfunction (the main group); 31 with normal body weight and regular menstrual cycle (the control group). Research methods: general clinical, biochemical (indicators of lipid and carbohydrate metabolism were determined), instrumental (ultrasound), statistical. Results. It was found that 53.3% of the girls from the main group had the beginning of the first menstruation after 14 years, delayed menstruation from 42 days to 6 days, duration 2.1 ± 0.05 days, which was significantly shorter, the volume of 10.2 ± 0.05; 0.4 points (average 1-2 pads per day) was significantly lower (p <0.05). Ultrasound showed uterine hypoplasia in almost every second girl in the main group - 36 (45.46%). Hyperleptinemia and leptin resistance was found in obesity of the first degree 34.8 ± 1.75, in obesity of the second degree 37.15 ± 2.12, in obesity of the third degree 40.64 ± 2.0. It was 14.35 ng / ml in the control group, p<0,01. Hyperleptinemia in the main group was accompanied by hyperinsulinemia in 26% of cases and insulin resistance. The relationship between low values of adiponectin and elevated body mass index in patients of the main group was established, which was confirmed by the results of correlation analysis (adiponectin & body mass index: ρ = -0.74). Analysis of the results revealed a decrease of A/L level in the main group by 4.3 times. Based on our own results, the A/L and HOMA-AD models can be considered more accurate for determining insulin resistance. Conclusions. 1. Changes of the menstrual cycle in overweight girls were found. The association of adipokines secretion disorders is characterized by hyperleptinemia, leptin resistance, decreased Adiponectin / Leptin index and hypoadiponectinemia, which, in combination with insulin resistance, indicates the participation of adipokines in the genesis of oligomenorrhea. The algorithm of adolescents’ treatment with menstrual dysfunction on the background of obesity must include the calculation of Adiponectin/Leptin and HOMA-AD, which will make it possible to avoid overdiagnosis of insulin resistance.

Alteration of serum leptin and LEP/LEPR promoter methylation in Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed but maternally imprinted genes in chromosome region 15q11-13. During child development, PWS usually results in insatiable appetite with subsequent obesity representing the major mortality factor. The neurobiological basis of PWS-typical hyperphagia has remained poorly understood. Many PWS-typical abnormalities are based on hypothalamic dysregulation, the region in which hunger and satiety are hormonally regulated, with the hormone leptin being a main long-term regulator of satiety. Previous studies in PWS have inconsistently shown leptin alterations solely in early childhood, without investigating the leptin system on an epigenetic level. The present study investigates serum leptin levels (S-leptin) and methylation of the leptin (LEP) and leptin receptor gene (LEPR) promoter in 24 individuals with PWS compared to 13 healthy controls matched for sex, age, and body mass index (BMI) and relates the results to the extent of hyperphagia in PWS. S-Leptin levels were obtained by Enzyme-linked Immunosorbent Assay. LEP/LEPR-promoter methylation was assessed by DNA-bisulfite-sequencing, hyperphagia by Hyperphagia Questionnaire for Clinical Trials (HQ-CT). PWS and control groups differed significantly in S-leptin levels with higher S-leptin in PWS. Methylation analysis showed significant differences in mean promoter methylation rate both for LEP and LEPR with a lower methylation rate in PWS. LEPR, but not LEP methylation correlated with S-leptin levels. S-leptin and both LEP and LEPR methylation did not correlate with HQ-CT scores in PWS. The present study is the first to show significantly elevated S-leptin levels in an adult PWS cohort combined with an altered, downregulated LEP and LEPR promoter methylation status compared to BMI-matched controls. Analogous to previous studies, no link to the behavioral dimension could be drawn. Overall, the results suggest an increased leptin dysregulation in PWS, whereby the findings partly mirror leptin resistance seen in non-syndromic obesity.

The Leptin System and Diet: A Mini Review of the Current Evidence

Leptin promotes satiety and modulates energy balance and weight. Diet-induced obesity leads to leptin resistance, exacerbating overeating. We reviewed the literature on the relationship between diet and leptin, which suggests that addressing leptin resistance through dietary interventions can contribute counteracting obesity. Albeit some limitations (e.g., limited rigor, small samples sizes), studies in animals and humans show that diets high in fat, carbohydrates, fructose, and sucrose, and low in protein are drivers of leptin resistance. Despite methodological heterogeneity pertaining to this body of literature, experimental studies show that energy-restricted diets can reduce leptinemia both in the short and long term and potentially reverse leptin resistance in humans. We also discuss limitations of this evidence, future lines of research, and implications for clinical and public health translations. Main limitations include the lack of a single universally-accepted definition of leptin resistance, and of adequate ways to accurately measure it in humans. The use of leptin sensitizers (drugs) and genetically individualized diets are alternatives against leptin resistance that should be further researched in humans. The tested very-low-energy intervention diets are challenging to translate into wide clinical or population recommendations. In conclusion, the link between nutritional components and leptin resistance, as well as research indicating that this condition is reversible, emphasizes the potential of diet to recover sensitivity to this hormone. A harmonized definition of leptin resistance, reliable methods to measure it, and large-scale, translational, clinical, and precision nutrition research involving rigorous methods are needed to benefit populations through these approaches.

Leptin Signaling in the Ovary of Diet-Induced Obese Mice Regulates Activation of NOD-Like Receptor Protein 3 Inflammasome

Obesity leads to ovarian dysfunction and the establishment of local leptin resistance. The aim of our study was to characterize the levels of NOD-like receptor protein 3 (NLRP3) inflammasome activation in ovaries and liver of mice during obesity progression. Furthermore, we tested the putative role of leptin on NLRP3 regulation in those organs. C57BL/6J female mice were treated with equine chorionic gonadotropin (eCG) or human chorionic gonadotropin (hCG) for estrous cycle synchronization and ovary collection. In diet-induced obesity (DIO) protocol, mice were fed chow diet (CD) or high-fat diet (HFD) for 4 or 16 weeks, whereas in the hyperleptinemic model (LEPT), mice were injected with leptin for 16 days (16 L) or saline (16 C). Finally, the genetic obese leptin-deficient ob/ob (+/? and −/−) mice were fed CD for 4 week. Either ovaries and liver were collected, as well as cumulus cells (CCs) after superovulation from DIO and LEPT. The estrus cycle synchronization protocol showed increased protein levels of NLRP3 and interleukin (IL)-18 in diestrus, with this stage used for further sample collections. In DIO, protein expression of NLRP3 inflammasome components was increased in 4 week HFD, but decreased in 16 week HFD. Moreover, NLRP3 and IL-1β were upregulated in 16 L and downregulated in ob/ob. Transcriptome analysis of CC showed common genes between LEPT and 4 week HFD modulating NLRP3 inflammasome. Liver analysis showed NLRP3 protein upregulation after 16 week HFD in DIO, but also its downregulation in ob/ob−/−. We showed the link between leptin signaling and NLRP3 inflammasome activation in the ovary throughout obesity progression in mice, elucidating the molecular mechanisms underpinning ovarian failure in maternal obesity.

Oxytocin as an Anti-obesity Treatment

Obesity is a growing health concern, as it increases risk for heart disease, hypertension, type 2 diabetes, cancer, COVID-19 related hospitalizations and mortality. However, current weight loss therapies are often associated with psychiatric or cardiovascular side effects or poor tolerability that limit their long-term use. The hypothalamic neuropeptide, oxytocin (OT), mediates a wide range of physiologic actions, which include reproductive behavior, formation of prosocial behaviors and control of body weight. We and others have shown that OT circumvents leptin resistance and elicits weight loss in diet-induced obese rodents and non-human primates by reducing both food intake and increasing energy expenditure (EE). Chronic intranasal OT also elicits promising effects on weight loss in obese humans. This review evaluates the potential use of OT as a therapeutic strategy to treat obesity in rodents, non-human primates, and humans, and identifies potential mechanisms that mediate this effect.

261 Effects of Dam Nutrition on Offspring Metabolism

Maternal diet during gestation is important for proper fetal growth and development. There is evidence that poor maternal nutrition (restricted- and over-feeding) can alter growth of the fetus with long-term consequences on postnatal growth and adult maintenance. Additionally, maternal diet can program offspring for altered metabolism which leads to increased fat deposition and likely reduced efficiency of production later in life. Using livestock models, we and others have demonstrated insulin resistance, leptin resistance, and increased adiposity in response to poor maternal nutrition. These systemic changes are likely due to altered metabolic regulation at the tissue level. Using a sheep model, we have evidence that poor maternal nutrition also alters key metabolic profiles in muscle and liver, key metabolic tissues, in offspring. Specifically, in offspring of restricted-fed ewes, similar profiles of amino acid (e.g. branched-chain amino acids, histidine, methionine) and lipid (e.g. triglycerides) metabolites were altered in blood, liver, and muscle. In the muscle of offspring from restricted- and over-fed ewes, lipid and protein metabolic profiles diverged between the two treatment groups. This demonstrates different mechanisms contributing to altered metabolism of offspring from ewes restricted- and over-fed during gestation. The similar changes in metabolic profiles at both the systemic and local level suggest complex mechanisms involved in metabolic dysregulation of offspring from poorly fed mothers, which likely contribute to life-long metabolic dysregulation and reduced efficiency of growth and product quality.