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Gene expression of adiponectin , the receptor AdipoR , and the adaptor protein APPL1 in the ARC of either ad libitum or food- deprived mice. Adiponectin , AdipoR1 , and APPL1 gene expression in the ARC is regulated by feeding status whereas AdipoR2 is unchanged. Autoradiographs depicting in situ hybridization with antisense 35 S-
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Adiponectin, an adipocyte-derived hormone, regulates glucose and lipid metabolism. It is also anti-inflammatory. During obesity, adiponectin levels and sensitivity are reduced. While the action of adiponectin in the periphery is well established the neuroendocrine role of adiponectin is largely unknown. To address this we analyzed the expression of...
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Context 1
... level of gene expression of adiponectin, AdipoR1 and APPL1 in the ARC was dependent on the feeding status of the mice, whereas AdipoR2 was unchanged (Fig- ure 1). In ad libitum fed wild-type mice, adiponectin ex- pression was detected in the hypothalamic ARC. ...
Context 2
... expression of AdipoR1 and APPL1 in the ARC was increased in fasted mice compared with ad libitum fed controls, whereas ex- pression of AdipoR2 was not affected by diet (n 7 mice per group; ad libitum vs food deprived P .051). APPL1 gene expression was also elevated by fasting in the VMH compared with ad libitum fed mice (Supplemental Figure 1; P .047), whereas the hybridization signal for the adiponectin receptors in the VMH could not be analyzed because it was beyond the sensitivity of the assay. ...
Context 3
... magnitude of changes in mRNA expression was 1.8-fold for AdipoR1 (P .039; Figure 1b) and 4-fold for APPL1 (P .019; Figure 1c) in food-deprived mice compared with controls. ...
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Citations
... Hence, the decrease of adiponectin in high-fructose-fed rats might represent a further molecular contribution to hypothalamic inflammation, also depriving this region of protection against the pro-oxidant effect of inflammatory cytokines. Although recent studies demonstrated adiponectin expression in the hypothalamus of mice, beavers, or female pigs [92][93][94][95], we cannot exclude that adipocytes are the source of the protein we measured in the hypothalamus. Indeed, peripheral adiponectin can cross the blood-brain barrier reaching the brain [96][97][98]. ...
Background:
The enhanced consumption of fructose as added sugar represents a major health concern. Due to the complexity and multiplicity of hypothalamic functions, we aim to point out early molecular alterations triggered by a sugar-rich diet throughout adolescence, and to verify their persistence until the young adulthood phase.
Methods:
Thirty days old rats received a high-fructose or control diet for 3 weeks. At the end of the experimental period, treated animals were switched to the control diet for further 3 weeks, and then analyzed in comparison with those that were fed the control diet for the entire experimental period.
Results:
Quantitative proteomics identified 19 differentially represented proteins, between control and fructose-fed groups, belonging to intermediate filament cytoskeleton, neurofilament, pore complex and mitochondrial respiratory chain complexes. Western blotting analysis confirmed proteomic data, evidencing a decreased abundance of mitochondrial respiratory complexes and voltage-dependent anion channel 1, the coregulator of mitochondrial biogenesis PGC-1α, and the protein subunit of neurofilaments α-internexin in fructose-fed rats. Diet-associated hypothalamic inflammation was also detected. Finally, the amount of brain-derived neurotrophic factor and its high-affinity receptor TrkB, as well as of synaptophysin, synaptotagmin, and post-synaptic protein PSD-95 was reduced in sugar-fed rats. Notably, deregulated levels of all proteins were fully rescued after switching to the control diet.
Conclusions:
A short-term fructose-rich diet in adolescent rats induces hypothalamic inflammation and highly affects mitochondrial and cytoskeletal compartments, as well as the level of specific markers of brain function; above-reported effects are reverted after switching animals to the control diet.
... Adiponectin is an adipocyte-derived hormone with anti-inflammatory and insulin-sensitizing effects. 61 The peripheral mechanism of adiponectin has been thoroughly studied, however, the regulation of central energy homeostasis and glucose metabolism remains unclear. Peripheral adiponectin can be transported to the brain through the blood-brain barrier. ...
Dan Yang,1,2 Xintong Hou,1,2 Guimei Yang,1,2 Mengnan Li,1,2 Jian Zhang,1,2 Minmin Han,1,2 Yi Zhang,3 Yunfeng Liu1 1Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2First Clinical Medical College, Shanxi Medical University, Taiyuan, People’s Republic of China; 3Department of Pharmacology, Shanxi Medical University, Taiyuan, People’s Republic of ChinaCorrespondence: Yi Zhang, Department of Pharmacology, Shanxi Medical University, Taiyuan, People’s Republic of China, Email yizhang313@163.com Yunfeng Liu, Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China, Tel +86 18703416196, Email nectarliu@163.comAbstract: The hypothalamus is indispensable in energy regulation and glucose homeostasis. Previous studies have shown that pro-opiomelanocortin neurons receive both central neuronal signals, such as α-melanocyte-stimulating hormone, β-endorphin, and adrenocorticotropic hormone, as well as sense peripheral signals such as leptin, insulin, adiponectin, glucagon-like peptide-1, and glucagon-like peptide-2, affecting glucose metabolism through their corresponding receptors and related signaling pathways. Abnormalities in these processes can lead to obesity, type 2 diabetes, and other metabolic diseases. However, the mechanisms by which these signal molecules fulfill their role remain unclear. Consequently, in this review, we explored the mechanisms of these hormones and signals on obesity and diabetes to suggest potential therapeutic targets for obesity-related metabolic diseases. Multi-drug combination therapy for obesity and diabetes is becoming a trend and requires further research to help patients to better control their blood glucose and improve their prognosis.Keywords: POMC neurons, central signals, peripheral signals, glucose homeostasis, obesity, diabetes
... However, adiponectin expression in the brain, and more specifically in the hypothalamus, is poorly documented. Indeed, a limited number of studies reported the expression of adiponectin in the hypothalamus of mice, beavers, or female pigs [25][26][27]. Even though a study reported the presence of adiponectin in the brain, it accumulated in the vascular endothelial cells and they concluded that adiponectin is not expressed by hypothalamic neural cells [28]. ...
... In the present work, we report the expression of adiponectin at both the mRNA and the protein levels in the hypothalamus of mice and more specifically in the MBH, and in two cell neuronal models. The expression of hypothalamic adiponectin was poorly documented [25][26][27]. We also confirmed the expression of its receptors in the MBH as we have previously reported [34]. ...
Peripheral adiponectin acts on the hypothalamus to inhibit energy expenditure and increase food intake through its receptors AdipoR1 and adipoR2. The hypothalamic expression of adiponectin is poorly documented. We hypothesize that whether hypothalamic adiponectin is confirmed, its expression and secretion could be regulated as peripheral adiponectin. Thus, in the present work, we aim to determine whether adiponectin is expressed in the hypothalamus and in two neuronal cell lines and investigate the potential mechanisms regulating its neuronal expression. Using immunohistochemistry, we show that adiponectin is expressed in the mediobasal hypothalamic neurons of mice. Adiponectin expression is also evidenced in two neuronal cell lines mHypo POMC (an adult mouse hypothalamic cell line) and SH-SY5Y (human neuroblastoma). The neuronal expression of adiponectin is increased in response to rosiglitazone treatment (a PPARγ agonist) and FGF21 and is decreased in insulin-resistant neurons. Furthermore, we show that adiponectin expressed by mHypo POMC neurons is secreted in a culture medium. Adiponectin also diminished the resistin-induced IL6 expression in SIMA9 cells, a microglia cell line. In conclusion, we evidenced the hypothalamic expression of adiponectin and its regulation at the neuronal level.
... adiponectin administration enhances both insulin and leptin intracellular signaling pathways, reduces food intake, and increases the expression of IRS1/2, JAK2 and STAT, furthermore adiponectin depolarizes Ob-R expressing POMC neurons and even potentiates its response to leptin (Sun et al. 2016). Furthermore, in genetically and diet-induced obese mice i.c.v adiponectin enhances glucose tolerance (Koch et al. 2014). It has also been suggested that in obesity adiponectin transport into the brain is also impaired (Kos et al. 2007). ...
The olfactory system is responsible for the reception, integration and interpretation of odors. However, in the last years, it has been discovered that the olfactory perception of food can rapidly modulate the activity of hypothalamic neurons involved in the regulation of energy balance. Conversely, the hormonal signals derived from changes in the metabolic status of the body can also change the sensitivity of the olfactory system, suggesting that the bidirectional relationship established between the olfactory and the hypothalamic systems is key for the maintenance of metabolic homeostasis. In the first part of this review, we describe the possible mechanisms and anatomical pathways involved in the modulation of energy balance regulated by the olfactory system. Hence, we propose a model to explain its implication in the maintenance of the metabolic homeostasis of the organism. In the second part, we discuss how the olfactory system could be involved in the development of metabolic diseases such as obesity and type two diabetes and, finally, we propose the use of intranasal therapies aimed to regulate and improve the activity of the olfactory system that in turn will be able to control the neuronal activity of hypothalamic centers to prevent or ameliorate metabolic diseases.
... Based on the anti-inflammatory effects of adiponectin, its increased levels in the hypothalamus may explain, at least in part, the lack of a central inflammatory response in the HFD group (Huang et al., 2008;Nigro et al., 2014). In line with this finding, an intracerebroventricular injection of adiponectin was able to reverse the elevated proinflammatory signals in the hypothalamus of HFD mice, reinforcing adiponectin anti-inflammatory role in the brain in the obesity context (Koch et al., 2014). ...
Obesity is a multifactorial disease, which in turn contributes to the onset of comorbidities, such as diabetes and atherosclerosis. Moreover, there are only few options available for treating obesity, and most current pharmacotherapy causes severe adverse effects, while offering minimal weight loss. Literature shows that metabotropic glutamate receptor 5 (mGluR5) modulates central reward pathways. Herein, we evaluated the effect of VU0409106, a negative allosteric modulator (NAM) of mGluR5 in regulating feeding and obesity parameters. Diet-induced obese C57BL/6 mice were treated for 14 days with VU0409106, and food intake, body weight, inflammatory/hormonal levels, and behavioral tests were performed. Our data suggest reduction of feeding, body weight, and adipose tissue inflammation in mice treated with high-fat diet (HFD) after chronic treatment with VU0409106. Furthermore, a negative modulation of mGluR5 also reduces binge-like eating, the most common type of eating disorder. Altogether, our results pointed out mGluR5 as a potential target for treating obesity, as well as related disorders.
... Under normal metabolic conditions ADIPOQ is one of the most abundant hormones in the blood with potent anti-inflammatory, insulin sensitizing, and appetite-regulatory properties (Koch et al., 2014;Yamauchi and Kadowaki, 2013). ADIPOQ receptor and receptor target gene expression in the MBH shows circadian rhythmicity (Cedernaes et al., 2019a;Kohsaka et al., 2007;Zhang et al., 2014). ...
Endogenous circadian clocks have evolved to anticipate 24 hr rhythms in environmental demands. Recent studies suggest that circadian rhythm disruption is a major risk factor for the development of metabolic disorders in humans. Conversely, alterations in energy state can disrupt circadian rhythms of behavior and physiology, creating a vicious circle of metabolic dysfunction. How peripheral energy state affects diurnal food intake, however, is still poorly understood. We here show that the adipokine adiponectin (ADIPOQ) regulates diurnal feeding rhythms through clocks in energy regulatory centers of the mediobasal hypothalamus (MBH). Adipoq-deficient mice show increased rest phase food intake associated with disrupted transcript rhythms of clock and appetite-regulating genes in the MBH. ADIPOQ regulates MBH clocks via AdipoR1-mediated upregulation of the core clock gene Bmal1. BMAL1, in turn, controls expression of orexigenic neuropeptide expression in the MBH. Together, these data reveal a systemic metabolic circuit to regulate central circadian clocks and energy intake.
... Under normal metabolic conditions ADIPOQ is one of the most abundant hormones in the blood with potent anti-inflammatory, insulin sensitizing, and appetite-regulatory properties (Koch et al., 2014;Yamauchi and Kadowaki, 2013). ADIPOQ receptor and receptor target gene expression in the MBH shows circadian rhythmicity (Cedernaes et al., 2019a;Kohsaka et al., 2007;Zhang et al., 2014). ...
Endogenous circadian clocks have evolved to anticipate 24 hr rhythms in environmental demands. Recent studies suggest that circadian rhythm disruption is a major risk factor for the development of metabolic disorders in humans. Conversely, alterations in energy state can disrupt circadian rhythms of behavior and physiology, creating a vicious circle of metabolic dysfunction. How peripheral energy state affects diurnal food intake, however, is still poorly understood. We here show that the adipokine adiponectin (ADIPOQ) regulates diurnal feeding rhythms through clocks in energy regulatory centers of the mediobasal hypothalamus (MBH). Adipoq-deficient mice show increased rest phase food intake associated with disrupted transcript rhythms of clock and appetite-regulating genes in the MBH. ADIPOQ regulates MBH clocks via AdipoR1-mediated upregulation of the core clock gene Bmal1. BMAL1, in turn, controls expression of orexigenic neuropeptide expression in the MBH. Together, these data reveal a systemic metabolic circuit to regulate central circadian clocks and energy intake.
... Adiponectin, an adipokine derived from adipose tissue, has been reported as beneficial in alleviating multiple physiological disturbances [7][8][9]. It helps in alleviating a variety of metabolic diseases by ameliorating the cellular stresses including inflammation, oxidative stress, and endoplasmic reticulum stress [7,8,[10][11][12]. ...
... Adiponectin, an adipokine derived from adipose tissue, has been reported as beneficial in alleviating multiple physiological disturbances [7][8][9]. It helps in alleviating a variety of metabolic diseases by ameliorating the cellular stresses including inflammation, oxidative stress, and endoplasmic reticulum stress [7,8,[10][11][12]. Although, a recent study identified an anti-inflammatory effect of adiponectin in the CNS [11], the role of adiponectin in rectifying the hypothalamic inflammation during early over-nutrition period remains elusive. ...
Adiponectin, an adipokine derived from the adipose tissue, manifests anti-inflammatory effects in the metabolically active organs and is, therefore, beneficial in various metabolic diseases associated with inflammation. However, the role of adiponectin in alleviating the hypothalamic inflammation connected to the pathogenesis of obesity has not yet been clearly interrogated. Here, we identified that the systemic administration of adiponectin suppresses the activation of microglia and thereby reverses the hypothalamic inflammation during short-term exposure to a high-fat diet. Additionally, we show that adiponectin induces anti-inflammatory effects in the microglial cell line subjected to an exogenous treatment with a saturated free fatty acid. In conclusion, the current study suggests that adiponectin suppresses the saturated free fatty acid-triggered the hypothalamic inflammation by modulating the microglial activation and thus maintains energy homeostasis.
... Adiponectin receptors (AdipoR) are widely expressed in rodent brains, including the hypothalamus, brainstem, prefrontal cortex, and hippocampus, suggesting its role in the CNS in addition to its role in metabolism [27,139,[151][152][153][154][155][156][157][158][159]. Overnight fasting by food deprivation for sixteen hours concomitantly downregulates mRNA expression of adiponectin and upregulates mRNA expression levels of AdipoR1 and APPL1 in the hypothalamic ARC [160], a brain area in the mediobasal hypothalamus regulating energy and glucose homeostasis [161]. ...
First seen as a fat-storage tissue, the adipose tissue is considered as a critical player in the endocrine system. Precisely, adipose tissue can produce an array of bioactive factors, including cytokines, lipids, and extracellular vesicles, which target various systemic organ systems to regulate metabolism, homeostasis, and immune response. The global effects of adipokines on metabolic events are well defined, but their impacts on brain function and pathology remain poorly defined. Receptors of adipokines are widely expressed in the brain. Mounting evidence has shown that leptin and adiponectin can cross the blood-brain barrier, while evidence for newly identified adipokines is limited. Significantly, adipocyte secretion is liable to nutritional and metabolic states, where defective circuitry, impaired neuroplasticity, and elevated neuroinflammation are symptomatic. Essentially, neurotrophic and anti-inflammatory properties of adipokines underlie their neuroprotective roles in neurodegenerative diseases. Besides, adipocyte-secreted lipids in the bloodstream can act endocrine on the distant organs. In this article, we have reviewed five adipokines (leptin, adiponectin, chemerin, apelin, visfatin) and two lipokines (palmitoleic acid and lysophosphatidic acid) on their roles involving in eating behavior, neurotrophic and neuroprotective factors in the brain. Understanding and regulating these adipokines can lead to novel therapeutic strategies to counteract metabolic associated eating disorders and neurodegenerative diseases, thus promote brain health.
... Adiponectin receptors are expressed in multiple brain regions, such as hypothalamus (Kubota et al., 2007), ventral tegmental area (Sun et al., 2018), PFC, hippocampus, and amygdala (Liu et al., 2012). In the hypothalamus, adiponectin modulates metabolism and food intake (Kubota et al., 2007;Qi et al., 2004) by activating or inhibiting proopiomelanocortin neurons excitability in response to low and high glucose levels (Koch et al., 2014;Suyama et al., 2016). On the other hand, adiponectin increases energy expenditure and thermogenesis, reduces blood glucose and insulin levels as part of its anti-diabetic properties (Qi et al., 2004), and reduces food intake (Coope et al., 2008). ...
A sedentary lifestyle is now known as a critical risk factor for accelerated aging-related neurodegenerative disorders. In contract, having regular physical exercise has opposite effects. Clinical findings have suggested that physical exercise can promote brain plasticity, particularly the hippocampus and the prefrontal cortex, that are important for learning and memory and mood regulations. However, the underlying mechanisms are still unclear. Animal studies reveal that the effects of physical exercise on promoting neuroplasticity could be mediated by different exerkines derived from the peripheral system and the brain itself. This book chapter summarizes the recent evidence from clinical and pre-clinical studies showing the emerging mediators for exercise-promoted brain health, including myokines secreted from skeletal muscles, adipokines from adipose tissues, and other factors secreted from the bone and liver.
