Role of leptin in early metabolic programming

Experimental studies in rodents have highlighted the relationship between early postnatal events, undernutrition during pregnancy and/or lactation and the subsequent development of metabolic syndrome, a phenomenon termed developmental programming. However, appearance of metabolic syndrome is dependent not only on prenatal or postnatal predisposition but also on type of nutrition throughout the life cycle. Those experimental findings have been supported by epidemiological data in humans, born to mothers who suffered undernutrition during pregnancy. Leptin is likely involved is such programming and maintaining a critical leptin level during development may allow normal maturation of tissues and pathways involved in metabolic homeostasis, reversing the undesired effects. Leptin disruption during a critical neonatal or prenatal window is sufficient to permanently alter long-term metabolic regulation. Thus, in rodents (in the early postnatal phase), and likely in other species such as primates, and including humans (in the prenatal period), leptin plays a major role in the development of brain circuits which affect future developmental programming of metabolic disease. As postnatal nutritional or therapeutic intervention can ameliorate the consequences of developmental malprogramming, use of leptin as an additive to milk in infant formula which, in contrast to maternal milk, which is devoid of this protein, has been suggested. Alternatively, identification of potential factors elevating leptin levels in maternal milk may also be beneficial. In conclusion, the present data highlight the importance of leptin in the developmental induction of metabolic disease and offer exciting new strategies for therapeutic intervention, by either maternal or neonatal intervention or targeted nutritional manipulation in postnatal life.Adipobiology 2009; 1: 27-34

Resistin activity in mice and humans affecting obesity, insulin resistance and T2DM: Blocking resistin action by resistin antagonis

Resistin, that was originally discovered in 2001 is named for its capacity to resist insulin action shown mainly in mice. However, there is a controversial history regarding its role in the pathogenesis of insulin resistance and type 2 diabetes mellitus (T2DM) in humans as most of the research was based on association between resistin blood levels and T2DM or other pathologies and so far the pharmacological effect of recombinant resistin has not been tested in humans or even in primates. Resistin is a 12 kD cysteine-rich small protein acting as covalent dimer. Although human and mouse resistin genes and protein sequences share only approximately 60% homology, which is less than most hormones conserved across species, the genes are syntenic, with the mouse gene encoding resistin being located at a similar distance from the insulin receptor gene. Unlike mouse resistin which is mainly expressed in adipocytes, human resistin is synthesized predominantly in monocytes and macrophages, especially in the visceral adipose tissue. Resistin`s effects are mediated via paracrine and endocrine mechanisms of action through a receptor on the surface of target cells that remains controversial. Others and our study has shown that resistin interacts with the Toll-like receptor 4 (TLR4), however other putative receptors such as an isoform of decorin, mouse receptor tyrosine kinase-like orphan receptor 1 (ROR1) and adenylyl cyclase-associated protein 1 (CAP1) have been also proposed. Downstream targets of resistin provide indirect evidence for its function in intracellular pathways, involving impairment of insulin signaling, response to inflammation and proliferation. Despite the lack of in vivo data concerning the resistin receptor and signaling in primates or humans, there is a need to explore the inflammatory, metabolic and oncogenic effects of resistin on human diseases. To address this challenge we have recently developed resistin mutant (C6A), acting as resistin antagonist which in several in vitro bioassays inhibited resistin action and in mice fed high fat diet (HFD) reduced weight, visceral fat, restored insulin sensitivity and attenuated HFD-induced neuro inflammation

Development of superactive leptin antagonists and their potential use in research and medicine

Superactive leptin antagonists (D23L/L39A/D40A/F41A), mutants of mouse, human, rat or ovine leptons, were developed in our laboratory, expressed in E. coli, refolded and purified to homogeneity as monomeric proteins. Pegylation of leptin antagonists resulted in a potent and effective long-acting reagents suitable for in vivo studies. In the present review we summarize the possible use of leptin antagonists as (i) research reagents in the study of bone development, autoimmune diseases, metabolic syndrome and type 2 diabetes mellitus (T2DM) with particular emphasis on creation of a novel, fast and reversible model of metabolic syndrome and T2DM in mice, and (ii) possible leptin blockers in various human pathologies such as uremic cachexia, anti-inflammatory and anti-autoimmune diseases, and cancer. In conclusion, the recognition and mutagenesis of D23L of previously developed leptin antagonists (L39A/D40A/F41A) enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency.Adipobiology 2012; 4: 5-21

COVID-19 Severity in Obesity: Leptin and Inflammatory Cytokine Interplay in the Link Between High Morbidity and Mortality

Obesity is one of the foremost risk factors in coronavirus infection resulting in severe illness and mortality as the pandemic progresses. Obesity is a well-known predisposed chronic inflammatory condition. The dynamics of obesity and its impacts on immunity may change the disease severity of pneumonia, especially in acute respiratory distress syndrome, a primary cause of death from SARS-CoV-2 infection. The adipocytes of adipose tissue secret leptin in proportion to individuals’ body fat mass. An increase in circulating plasma leptin is a typical characteristic of obesity and correlates with a leptin-resistant state. Leptin is considered a pleiotropic molecule regulating appetite and immunity. In immunity, leptin functions as a cytokine and coordinates the host’s innate and adaptive responses by promoting the Th1 type of immune response. Leptin induced the proliferation and functions of antigen-presenting cells, monocytes, and T helper cells, subsequently influencing the pro-inflammatory cytokine secretion by these cells, such as TNF-α, IL-2, or IL-6. Leptin scarcity or resistance is linked with dysregulation of cytokine secretion leading to autoimmune disorders, inflammatory responses, and increased susceptibility towards infectious diseases. Therefore, leptin activity by leptin long-lasting super active antagonist’s dysregulation in patients with obesity might contribute to high mortality rates in these patients during SARS-CoV-2 infection. This review systematically discusses the interplay mechanism between leptin and inflammatory cytokines and their contribution to the fatal outcomes in COVID-19 patients with obesity

Chronic central leptin infusion differently modulates brain and liver insulin signaling.

International audienceRecent studies reported the impact of leptin on peripheral insulin sensitivity and glucose utilization. However, little is known concerning the effect of central leptin on hypothalamic and hepatic insulin efficiency. This study aimed to determine the consequence of chronic intra-cerebroventricular (ICV) leptin or murine leptin antagonist (MLA) infusion on hypothalamic and hepatic insulin signaling pathways, in rats. A 2-week central leptin infusion enhanced insulin-dependent Akt phosphorylation in the liver without changing PTP-1B protein expression, associated to insulin receptor (IR) upregulation and reduced IRS-1 phosphorylation on Ser302 residue. In the hypothalamus, a chronic ICV leptin infusion induced PTP-1B associated with a specific decrease in insulin-dependent Akt phosphorylation. In contrast, a chronic MLA infusion did not alter IR and PTP-1B expressions in hypothalamus and liver. Our results underline a brain leptin-dependent increase in hepatic insulin efficiency as mirrored by IR up-regulation, increased insulin-dependent Akt phosphorylation and reduced IRS-1 phosphorylation on Ser302 residue

The regulation of stearoyl-coa desaturase gene expression is tissue specific in chickens.

International audienceEmerging evidence suggests a potential role of stearoyl-CoA desaturase (SCD)-1 in the control of body weight and energy homeostasis. The present study was conducted to investigate the effects of several energy balance-related factors (leptin, cerulenin, food deprivation, genotype, and gender) on SCD gene expression in chickens. In experiment 1, 6-week-old female and male broiler chickens were used. In experiment 2, two groups of 3-week-old broiler chickens were continuously infused with recombinant chicken leptin (8 micro g/kg/h) or vehicle for 6 h. In experiment 3, two groups of 2-week-old broiler chickens received i.v. injections of cerulenin (15 mg/kg) or vehicle. In experiment 4, two broiler chicken lines (fat and lean) were submitted to two nutritional states (food deprivation for 16 or 24 h and feeding ad libitum). At the end of each experiment, tissues were collected for analyzing SCD gene expression. Data from experiment 1 showed that SCD is ubiquitously expressed in chicken tissues with highest levels in the proventriculus followed by the ovary, hypothalamus, kidney, liver, and adipose tissue in female, and hypothalamus, leg muscle, pancreas, liver, and adipose tissue in male. Female chickens exhibited significantly higher SCD mRNA levels in kidney, breast muscle, proventriculus, and intestine than male chickens. However, hypothalamic SCD gene expression was higher in male than in female (P < 0.05). Leptin increased SCD gene expression in chicken liver (P < 0.05), whereas cerulenin decreased SCD mRNA levels in muscle. Both leptin and cerulenin significantly reduced food intake (P < 0.05). Food deprivation for either 16 or 24 h decreased the hepatic SCD gene expression in fat line and lean line chickens compared with their fed counterparts (P < 0.05). The hypothalamic SCD mRNA levels were decreased in both lines only after 24 h of food deprivation (P < 0.05). In conclusion, SCD is ubiquitously expressed in chickens and it is regulated by leptin, cerulenin, nutritional state, and gender in a tissue-specific manner