hypothalamic-kisspeptin-neurons-as-target-for-whole-cell-patch-clamp

Hypothalamic Kisspeptin Neurons as a Target for Whole-Cell Patch-Clamp Recordings

Kisspeptins are essential for the maturation of the hypothalamic-pituitary-gonadal (HPG) axis and fertility. Hypothalamic kisspeptin neurons located in ...

Universidade de Sao Paulo

Several studies showed that l-leucine supplementation reduces adiposity when provided before the onset of obesity. We studied rats that were exposed to a high-fat diet (HFD) for 10 weeks before they started to receive l-leucine supplementation. Fat mass was increased in l-leucine-supplemented rats consuming the HFD. Accordingly, l-leucine produced a hypothalamic pattern of gene expression that favors fat accumulation. In conclusion, l-leucine supplementation worsened the adiposity of rats previously exposed to HFD possibly by central mechanisms.

L-leucine supplementation worsens the adiposity of already obese rats by promoting a hypothalamic pattern of gene expression that favors fat accumulation.

Leucine is a well-known activator of the mammalian target of rapamycin (mTOR). Because mTOR signaling regulates several aspects of metabolism, the potential of leucine as a dietary supplement for treating obesity and diabetes mellitus has been investigated. The objective of the present review was to summarize and discuss the available evidence regarding the mechanisms and the effects of leucine supplementation on the regulation of food intake, energy balance, and glucose homeostasis. Based on the available evidence, we conclude that although central leucine injection decreases food intake, this effect is not well reproduced when leucine is provided as a dietary supplement. Consequently, no robust evidence indicates that oral leucine supplementation significantly affects food intake, although several studies have shown that leucine supplementation may help to decrease body adiposity in specific conditions. However, more studies are necessary to assess the effects of leucine supplementation in already-obese subjects. Finally, although several studies have found that leucine supplementation improves glucose homeostasis, the underlying mechanisms involved in these potential beneficial effects remain unknown and may be partially dependent on weight loss.

Reviewing the Effects of L-Leucine Supplementation in the Regulation of Food Intake, Energy Balance, and Glucose Homeostasis.

Pregnancy induces transitory metabolic changes including increases in food intake and body fat deposition, as well as leptin and insulin resistance. Recent findings have suggested that increased hypothalamic expression of suppressor of cytokine signaling-3 (SOCS3) is a key mechanism responsible for triggering those metabolic adaptations. Because obesity is a risk factor for gestational metabolic imbalances, we aimed to study the role of SOCS3 during pregnancy in obese mice. Female mice carrying a deletion of SOCS3 in leptin receptor-expressing cells (SOCS3 KO mice) were exposed to a chronic high-fat diet (HFD), and we then studied their energy balance and glucose homeostasis during pregnancy. SOCS3 deletion did not prevent diet-induced obesity or changes in body weight and adiposity observed during pregnancy. However, the typical increase in food intake during mid- and late-pregnancy was blunted in SOCS3 KO females. We also observed a slight improvement in glucose homeostasis and increased leptin sensitivity in the arcuate nucleus of the hypothalamus in pregnant SOCS3 KO mice on HFD. Despite this, SOCS3 KO mice had an increased number of uterine reabsorptions and fewer fetuses compared to the controls. Compared to control animals, a reduction in proopiomelanocortin and an increase in oxytocin mRNA levels were observed in the hypothalamus of pregnant SOCS3 KO mice. In contrast to previous studies using lean animals, conditional SOCS3 ablation did not prevent major gestational metabolic changes in diet-induced obese mice. Our findings contribute to the understanding of the role of SOCS3 in mediating pregnancy-induced metabolic adaptations.

SOCS3 expression within leptin receptor-expressing cells regulates food intake and leptin sensitivity but does not affect weight gain in pregnant mice consuming a high-fat diet.

Leptin resistance is a hallmark of obesity. Treatments aiming to improve leptin sensitivity are considered a promising therapeutical approach against obesity. However, leptin receptor (LepR) signaling also modulates several neurovegetative aspects, such as the cardiovascular system and hepatic gluconeogenesis. Thus, we investigated the long-term consequences of increased leptin sensitivity, considering the potential beneficial and deleterious effects. To generate a mouse model with increased leptin sensitivity, the suppressor of cytokine signaling 3 (SOCS3) was ablated in LepR-expressing cells (LepR mice). LepR mice displayed reduced food intake, body adiposity and weight gain, as well as improved glucose tolerance and insulin sensitivity, and were protected against aging-induced leptin resistance. Surprisingly, a very high mortality rate was observed in aging LepR mice. LepR mice showed cardiomyocyte hypertrophy, increased myocardial fibrosis and reduced cardiovascular capacity. LepR mice exhibited impaired post-ischemic cardiac functional recovery and middle-aged LepR mice showed substantial arhythmic events during the post-ischemic reperfusion period. Finally, LepR mice exhibited fasting-induced hypoglycemia and impaired counterregulatory response to glucopenia associated with reduced gluconeogenesis. In conclusion, although increased sensitivity to leptin improved the energy and glucose homeostasis of aging LepR mice, major autonomic/neurovegetative dysfunctions compromised the health and longevity of these animals. Consequently, these potentially negative aspects need to be considered in the therapies that increase leptin sensitivity chronically.

SOCS3 Ablation in Leptin Receptor-Expressing Cells Causes Autonomic and Cardiac Dysfunctions in Middle-Aged Mice despite Improving Energy and Glucose Metabolism.

Article	Year
L-leucine supplementation worsens the adiposity of already obese rats by promoting a hypothalamic pattern of gene expression that favors fat accumulation. Nutrients\| PubMed ID: 24699194	2014
Reviewing the Effects of L-Leucine Supplementation in the Regulation of Food Intake, Energy Balance, and Glucose Homeostasis. Nutrients\| PubMed ID: 26007339	2015
SOCS3 expression within leptin receptor-expressing cells regulates food intake and leptin sensitivity but does not affect weight gain in pregnant mice consuming a high-fat diet. Physiology & behavior\| PubMed ID: 26828039	2016
SOCS3 Ablation in Leptin Receptor-Expressing Cells Causes Autonomic and Cardiac Dysfunctions in Middle-Aged Mice despite Improving Energy and Glucose Metabolism. International journal of molecular sciences\| PubMed ID: 35742928	2022

Thais T. Zampieri

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