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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. Various cardiac properties, including QRS duration, R wave amplitude, heart rate (HR), ejection fraction (EF), end-diastolic left ventricular mass (EDLVM), end-diastolic volume (EDV), and cardiac output (CO) were analyzed. Central leptin infusion increased cardiac PPARβ/δ protein content and decreased HR, QRS duration, and R wave amplitude. These changes induced by central leptin suggested a decrease in the ventricular wall growth, which was confirmed by MRI. In fact, the EDLVM was reduced by central leptin while increased in rats co-treated with leptin and GSK0660, a selective antagonist of PPARβ/δ activity. In summary, central leptin plays a dual role in cardiac health, potentially leading to ventricular atrophy and improving heart function when PPARβ/δ signaling is intact. The protective effects of leptin are lost by PPARβ/δ inhibition, underscoring the importance of this pathway. These findings highlight the therapeutic potential of targeting leptin and PPARβ/δ pathways to combat cardiac alterations and heart failure, particularly in the context of obesity. [ABSTRACT FROM AUTHOR]

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. Herein, we analyzed the gene expression, protein and phosphorylation levels of hypothalamic enzymes and transcription factors related to lipid metabolism. Experiments were performed in male Wistar rats of 3-, 8- and 24-month-old Wistar rats fed ad libitum (AL), as ageing model. Besides, 5- and 21-month-old rats were subjected to a moderate FR protocol (equivalent to ≈ 80% of normal food intake) for three months before the sacrifice. Aged Wistar rats showed a situation of chronic lipid excess as a result of an increase in de novo FA synthesis and FA levels that reach the brain, contributing likely to the development of central leptin and insulin resistance. We observe a hypothalamic downregulation of AMP-activated protein kinase (AMPK) and stearoyl-CoA desaturase (SCD1) and an increase of carnitine palmitoyltransferase-1c (CPT1c) expression. Our results suggest an impairment in the physiological lipid sensing system of aged Wistar rats, which would alter the balance of the intracellular mobilization and trafficking of lipids between the mitochondria and the Endoplasmic Reticulum (ER) in the hypothalamus, leading probably to the development of neurolipotoxicity in aged rats. Lastly, FR can only partially restore this imbalance. Schematic representation of the fate of LCFA-CoA in the hypothalamus of young and old rats. Blood circulating LCFAs in young Wistar rats reach the hypothalamus, where they are esterified to LCFA-CoA. Into glial cells or neurons, LCFA-CoA are driven to mitochondria (CPT1a) or ER (CPT1c) where could be desaturated by SDC1 and, thereby, converted into structural and signaling unsaturated lipids as oleic acid, related with neuronal myelinization and differentiation. However, the excess of LCFA that reach to the hypothalamus in old animals, could generate an increase in LCFA-CoA, which together with an increase in CPT1c levels, could favor the capture of LCFA-CoA to the ER. The decrease in the levels of SCD1 in old rats would decrease FA unsaturation degree that could trigger lipotoxicity process and neurodegeneration, both related to the development of neurodegenerative diseases linked to age. [ABSTRACT FROM AUTHOR]

Abstract: Invertebrate metallothioneins (MT) have mainly been reported in digestive tissues, but data about the existence of a ubiquitous isoform expressed also in nervous tissue, are not available. Here we report the identification of a new metallothionein gene (MTPA) from the lobster Panulirus argus, putatively encoding a 59 residue polypeptide including 19 Cys. Tissue specific analysis indicated that MTPA is ubiquitously expressed in the hepatopancreas, intestine, nervous tissue and muscle, with the highest levels in the hepatopancreas and the lowest in muscle and nervous tissue. In addition, our data showed that MTPA is differentially regulated by metals: tissue explants exposed to Cd exhibited increased MTPA mRNA levels in all cases, except in muscle, with the highest effects in the nervous tissue, while Zn was effective only in the hepatopancreas. Interestingly, Cu showed no effects in any of the analyzed tissues. Taken together, these results suggest that MTPA in the hepatopancreas likely plays an important role in Cd detoxification and Zn homeostasis. The potent Cd-inducibility of MTPA in the nervous tissue might suggest a key function of this protein in protecting this highly sensitive tissue from cadmium-induced neurotoxicity. [Copyright &y& Elsevier]

The hypothalamus integrates peripheral signals and modulates food intake and energy expenditure by regulating the metabolic function of peripheral tissues, including the liver and adipose tissue. In a previous study, we demonstrated that s-resistin, an intracellular resistin isoform highly expressed in the hypothalamus and upregulated during aging, is important in the central control of energy homeostasis, affecting mainly the peripheral response to insulin by still unknown mechanisms. Herein, using an intracerebroventricular injection of a specific lentiviral RNAi against s-resistin, we assessed, in the Wistar rat, the effects of central s-resistin downregulation on the expression and phosphorylation levels of intermediates involved in insulin signaling and the inflammatory response in epididymal white adipose tissue (eWAT) and liver. Additionally, we studied the imbalance of eWAT hypertrophy/hyperplasia remodeling. Our results indicate that central downregulation of s-resistin regulates insulin signaling cascade in a tissue-specific manner, reduces the inflammatory status both in the liver and eWAT, and prevents eWAT hypertrophy. Taken together, our results highlight the pivotal role of central s-resistin in maintaining metabolic homeostasis in AT and the liver. This suggests a direct association between its function and the modulation of the inflammatory response in these tissues., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.)

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. Even insulin action on peripheral target tissues has been recently demonstrated to be partially mediated by its central action, suggesting that a decrease in central insulin action could be involved in the development of peripheral insulin resistance. In the present review we analyze the available research data on aging-associated insulin resistance making emphasis in the following aspects: 1) The time-course of development of overall insulin resistance and the evolution of changes in circulating adipokines; 2) The effect of caloric restriction and the decrease of adiposity in insulin action; 3) The influence of changes in the central action of factors like leptin or insulin in the development and maintenance of insulin resistance during aging.