Central Actions of Leptin Induce an Atrophic Pattern and Improves Heart Function in Lean Normoleptinemic Rats via PPARβ/δ Activation.

Leptin, acting centrally or peripherally, has complex effects on cardiac remodeling and heart function. We previously reported that central leptin exerts an anti-hypertrophic effect in the heart via cardiac PPARβ/δ activation. Here, we assessed the impact of central leptin administration and PPARβ/δ inhibition on cardiac function.

Central leptin signaling deficiency induced by leptin receptor antagonist leads to hypothalamic proteomic remodeling.

Aims: Leptin irresponsiveness, which is often associated with obesity, can have significant impacts on the hypothalamic proteome of individuals, including those who are lean. While mounting evidence on leptin irresponsiveness has focused on obese individuals, understanding the early molecular and proteomic changes associated with deficient hypothalamic leptin signaling in lean individuals is essential for early intervention and prevention of metabolic disorders. Leptin receptor antagonists block the binding of leptin to its receptors, potentially reducing its effects and used in cases where excessive leptin activity might be harmful.

Unbiased Phosphoproteome Mining Reveals New Functional Sites of Metabolite-Derived PTMs Involved in MASLD Development.

Post-translational modifications (PTMs) of proteins are paramount in health and disease. Phosphoproteome analysis by enrichment techniques is becoming increasingly attractive for biomedical research. Recent findings show co-enrichment of other phosphate-containing biologically relevant PTMs, but these results were obtained by closed searches focused on the modifications sought.

Grape seed extract supplementation modulates hepatic lipid metabolism in rats. Implication of PPARβ/δ.

In mammals, the liver is involved in nutrient metabolism and in the regulation of lipid and glucose homeostasis. Multiple studies have described improvements in liver disorders after regular consumption of grape seed extract (GSE). GSE prevents or ameliorates hepatic metabolic dysfunction through AMPK activation, which reduces hepatic lipogenesis while enhancing hepatic lipid oxidation.

Aging Induces Hepatic Oxidative Stress and Nuclear Proteomic Remodeling in Liver from Wistar Rats.

Aging is a continuous, universal, and irreversible process that determines progressive loss of adaptability. The liver is a critical organ that supports digestion, metabolism, immunity, detoxification, vitamin storage, and hormone signaling. Nevertheless, the relationship between aging and the development of liver diseases remains elusive.

Leptin, Acting at Central Level, Increases FGF21 Expression in White Adipose Tissue via PPARβ/δ.

The altered function of adipose tissue can result in obesity, insulin resistance, and its metabolic complications. Leptin, acting on the central nervous system, modifies the composition and function of adipose tissue. To date, the molecular changes that occur in epididymal white adipose tissue (eWAT) during chronic leptin treatment are not fully understood.

Ageing alters the lipid sensing process in the hypothalamus of Wistar rats. Effect of food restriction.

Introduction: Lipids regulate a wide range of biological processes. The mechanisms by which fatty acids (FA) and its metabolites influence the hypothalamic regulation of energy homeostasis have been highly studied. However, the effect of ageing and food restriction (FR) on this process is unknown.

The nutrient sensing pathways FoxO1/3 and mTOR in the heart are coordinately regulated by central leptin through PPARβ/δ. Implications in cardiac remodeling.

Background: Cardiovascular disease in obese individuals with type 2 diabetes is often associated with hyperleptinemia and leptin resistance, while other studies support that leptin has cardioprotective effects. Besides, the role of leptin in regulating cardiac atrophy or hypertrophy remains to be clearly defined. In fact, in rats with normal leptin sensitivity, the molecular underpinnings of the effects of central leptin regulating cardiac structural pathways remain poorly understood.

Effects of Moderate Chronic Food Restriction on the Development of Postprandial Dyslipidemia with Ageing.

Ageing is a major risk factor for the development of metabolic disorders linked to dyslipidemia, usually accompanied by increased adiposity. The goal of this work was to investigate whether avoiding an excessive increase in adiposity with ageing, via moderate chronic food restriction (FR), ameliorates postprandial dyslipidemia in a rat model of metabolic syndrome associated with ageing. Accordingly, we performed an oral lipid loading test (OLLT) in mature middle-aged (7 months) and middle-old-aged (24 months) Wistar rats fed ad libitum (AL) or under moderate FR for 3 months.

Changes in Visceral Adipose Tissue Plasma Membrane Lipid Composition in Old Rats Are Associated With Adipocyte Hypertrophy With Aging.

Increased adiposity, through adipocyte hypertrophy, and/or hyperplasia, characterizes aging and obesity. Both are leptin-resistant states, associated with disturbed lipid metabolism, reduced insulin sensitivity and inflammation. Nevertheless, fat tissue dysfunction appears earlier in obesity than in normal aging.

Food Restriction is Required to Preserve the Antisteatotic Effects of Central Leptin in the Liver of Middle-Aged Rats.

Objective: Aging is a significant risk factor for the development of obesity and hepatic steatosis associated with insulin and leptin resistance. Food restriction (FR) is commonly used for reducing body weight (BW), adiposity, and liver steatosis. Thus, this study aimed to determine whether FR in middle-aged rats can recover the central leptin antisteatotic effects observed in the liver in young animals.

Central leptin regulates heart lipid content by selectively increasing PPAR β/δ expression.

The role of central leptin in regulating the heart from lipid accumulation in lean leptin-sensitive animals has not been fully elucidated. Herein, we investigated the effects of central leptin infusion on the expression of genes involved in cardiac metabolism and its role in the control of myocardial triacylglyceride (TAG) accumulation in adult Wistar rats. Intracerebroventricular (icv) leptin infusion (0.

S-resistin, a non secretable resistin isoform, impairs the insulin signalling pathway in 3T3-L1 adipocytes.

S-resistin is a non-secretable resistin spliced variant, which is expressed mainly in the white adipose tissue from Wistar rats. Previous results confirmed that 3T3-L1 cells expressing s-resistin (3T3-L1-s-res) showed an inflammatory response and exhibited a decrease in glucose transport, both basal and insulin-stimulated. Here we present evidences demonstrating for the first time that s-resistin, like resistin, blocks insulin signalling pathway by inhibiting insulin receptor, insulin receptor substrate 1, protein kinase B/Akt and the mammalian target of rapamycin phosphorylation, and increasing the suppressor of cytokine signalling 3 levels being the later probably due to augmented of leptin expression.

Aging impairs the hepatic subcellular distribution of ChREBP in response to fasting/feeding in rats: Implications on hepatic steatosis.

Aging is associated with alterations of lipid metabolism and increased prevalence of non alcoholic hepatic steatosis. Nevertheless, the mechanisms by which fat is accumulated in the liver during aging remain incompletely understood. In the present study, we investigated potential alterations that might contribute to the development of hepatic steatosis with aging.

Development of insulin resistance during aging: involvement of central processes and role of adipokines.

Aging in mammals associates with the development of peripheral insulin resistance. Additionally, adiposity usually increases with aging and this could play a relevant role in the gradual impairment of insulin action. In fact, fat accretion leads to changes in the expression and circulating concentrations of factors originated in adipose tissue like leptin, resistin and inflammatory cytokines which have been shown to modulate insulin signaling in insulin target tissues acting both, directly or through the central nervous system.

Regulation of insulin-stimulated glucose uptake in rat white adipose tissue upon chronic central leptin infusion: effects on adiposity.

Leptin enhances the glucose utilization in most insulin target tissues and paradoxically decreases it in white adipose tissue (WAT), but knowledge of the mechanisms underlying the inhibitory effect of central leptin on the insulin-dependent glucose uptake in WAT is limited. After 7 d intracerebroventricular leptin treatment (0.2 μg/d) of rats, the overall insulin sensitivity and the responsiveness of WAT after acute in vivo insulin administration were analyzed.

S-resistin inhibits adipocyte differentiation and increases TNFalpha expression and secretion in 3T3-L1 cells.

S-resistin is a non-secretable resistin spliced variant described in white adipose tissue from Wistar rats. Since resistin has been implicated in adipogenesis regulation, here we have investigated the possible role of this new isoform in this process. For that, we have studied the adipocyte development in 3T3-L1 pre-adipocyte cell line stably expressing s-resistin and resistin.

The expression of rat resistin isoforms is differentially regulated in visceral adipose tissues: effects of aging and food restriction.

Two variants of the adipose hormone resistin are generated by alternative splicing in Wistar rats. Here we analyzed the expression of these resistin variants in 2 main visceral adipose depots, epididymal and retroperitoneal, as well as the resistin serum concentration during aging and food restriction. Total protein levels of resistin were also analyzed in extracts from both visceral adipose depots.

The effect of aging on insulin signalling pathway is tissue dependent: central role of adipose tissue in the insulin resistance of aging.

Insulin resistance progressively increases with age, resulting in excessively high incidence of T2D in the elderly population. To investigate the molecular mechanisms underlying insulin resistance of aging, we carried out a comparative study of insulin signalling cascade in adipose tissue, liver and skeletal muscle. We measured the protein levels in different subcellular compartments and the phosphorylation status of key components of the insulin signalling pathway in response to in vivo insulin infusion.

Central leptin regulates total ceramide content and sterol regulatory element binding protein-1C proteolytic maturation in rat white adipose tissue.

Obesity and type 2 diabetes are associated with insulin and leptin resistance, and increased ceramide contents in target tissues. Because the adipose tissue has become a central focus in these diseases, and leptin-induced increases in insulin sensitivity may be related to effects of leptin on lipid metabolism, we investigated herein whether central leptin was able to regulate total ceramide levels and the expression of enzymes involved in ceramide metabolism in rat white adipose tissue (WAT). After 7 d central leptin treatment, the total content of ceramides was analyzed by quantitative shotgun lipidomics mass spectrometry.

MTPA: a crustacean metallothionein that affects hepatopancreatic mitochondrial functions.

Metallothioneins are cysteine-rich proteins, with a high capacity to bind metallic ions, and for which a precise biological role has not been established. Here we investigated the effects of MTPA, a metallothionein from the lobster Panulirus argus, on mitochondrial oxygen consumption and ROS production. An HPLC-RP-ESI-MS analysis of recombinant MTPA showed that despite its extra Cys, MTPA binds 6 Zn2+ per molecule akin to other crustacean metallothioneins with 18 Cys.

Tissue-specific effects of central leptin on the expression of genes involved in lipid metabolism in liver and white adipose tissue.

Leptin reduces adiposity and exerts antisteatotic effects on nonadipose tissues. However, the mechanisms underlying leptin effects on lipid metabolism in liver and white adipose tissue have not been fully clarified. Here, we have studied the effects of central leptin administration on key enzymes and transcription factors involved in lipid metabolism in liver and epididymal adipose tissue.

Effect of age and moderate food restriction on insulin sensitivity in Wistar rats: role of adiposity.

Insulin resistance develops with ageing in humans and rodents. Here, we have studied the evolution of insulin sensitivity with ageing trying to discriminate the role of adiposity from that of ageing in this process. We performed oral glucose tolerance tests and determined overall and tissue-specific glucose utilization under euglycemic-hyper-insulinemic conditions in 3-, 8-, and 24-month-old rats fed ad libitum, and in 8- and 24-month-old rats after 3 months of calorie restriction.

Altered subcellular distribution of IRS-1 and IRS-3 is associated with defective Akt activation and GLUT4 translocation in insulin-resistant old rat adipocytes.

Insulin receptor signal transduction depends on the precise intracellular localization of signalling molecules. This study examines the compartmentalization and the insulin-induced translocation and tyrosine phosphorylation of insulin receptor substrates (IRS-1 and IRS-3) in epididymal white adipose tissue from adult and insulin-resistant old rats. We found that insulin induces the translocation of IRS-1 from plasma membrane (PM) and light microsomes (LM) to cytosol, whereas IRS-3 translocates from PM to LM and cytosol upon insulin stimulation.