Brain Adipocytokine Action and Metabolic Regulation

University of Pennsylvania School of Medicine, Division of Endocrinology, Diabetes and Metabolism, 764 Clinical Research Building, 415 Curie Blvd., Philadelphia, PA 19104, USA.
Diabetes (Impact Factor: 8.1). 01/2007; 55 Suppl 2(Suppl 2):S145-54. DOI: 10.2337/db06-S018
Source: PubMed


Adipose tissue secretes factors that control various physiological systems. The fall in leptin during fasting mediates hyperphagia and suppresses thermogenesis, thyroid and reproductive hormones, and immune system. On the other hand, rising leptin levels in the fed state stimulate fatty acid oxidation, decrease appetite, and limit weight gain. These divergent effects of leptin occur through neuronal circuits in the hypothalamus and other brain areas. Leptin also regulates the activities of enzymes involved in lipid metabolism, e.g., AMP-activated protein kinase and stearoyl-CoA desaturase-1, and also interacts with insulin signaling in the brain. Adiponectin enhances fatty acid oxidation and insulin sensitivity, in part by stimulating AMP-activated protein kinase phosphorylation and activity in liver and muscle. Moreover, adiponectin decreases body fat by increasing energy expenditure and lipid catabolism. These effects involve peripheral and possibly central mechanisms. Adipose tissue mediates interconversion of steroid hormones and secretes proinflammatory cytokines, vasoactive peptides, and coagulation and complement proteins. Understanding the actions of these "adipocytokines" will provide insight into the pathogenesis and treatment of obesity and related diseases.

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    • "Adiponectin modulates brain metabolism and sensitivity of insulin [1, 44] regulating memory and cognitive dysfunction [45] and it also regulates severe inflammaion observed in mild cognitive impairment and Alzheimer's disease [46-48]. In particular, adiponectin contributes to the deregulated glucose metabolism and mitochondrial dysfunction observed in Alzheimer's disease [49, 50]. "
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    ABSTRACT: Adiponectin is an adipocytokine released by the adipose tissue and has multiple roles in the immune system and in the metabolic syndromes such as cardiovascular disease, Type 2 diabetes, obesity and also in the neurodegenerative disorders including Alzheimer's disease. Adiponectin regulates the sensitivity of insulin, fatty acid catabolism, glucose homeostasis and anti-inflammatory system through various mechanisms. Previous studies demonstrated that adiponectin modulates memory and cognitive impairment and contributes to the deregulated glucose metabolism and mitochondrial dysfunction observed in Alzheimer's disease. Here, we aim to summarize recent studies that suggest the potential correlation between adiponectin and Alzheimer's disease.
    Full-text · Article · Dec 2013 · Anatomy & cell biology
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    • "The network β is enriched for genes related to adipocytokine signaling pathway. This molecular cascade is an important regulator of energy intake and metabolic rate [49]. It thus appears that glial cells use expression of network β genes to activate a set of metabolic control points and therefore, to support the functional responses of neurons to psychotropic drugs. "
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    ABSTRACT: Despite their widespread use, the biological mechanisms underlying the efficacy of psychotropic drugs are still incompletely known; improved understanding of these is essential for development of novel more effective drugs and rational design of therapy. Given the large number of psychotropic drugs available and their differential pharmacological effects, it would be important to establish specific predictors of response to various classes of drugs. To identify the molecular mechanisms that may initiate therapeutic effects, whole-genome expression profiling (using 324 Illumina Mouse WG-6 microarrays) of drug-induced alterations in the mouse brain was undertaken, with a focus on the time-course (1, 2, 4 and 8 h) of gene expression changes produced by eighteen major psychotropic drugs: antidepressants, antipsychotics, anxiolytics, psychostimulants and opioids. The resulting database is freely accessible at Bioinformatics approaches led to the identification of three main drug-responsive genomic networks and indicated neurobiological pathways that mediate the alterations in transcription. Each tested psychotropic drug was characterized by a unique gene network expression profile related to its neuropharmacological properties. Functional links that connect expression of the networks to the development of neuronal adaptations (MAPK signaling pathway), control of brain metabolism (adipocytokine pathway), and organization of cell projections (mTOR pathway) were found. The comparison of gene expression alterations between various drugs opened a new means to classify the different psychoactive compounds and to predict their cellular targets; this is well exemplified in the case of tianeptine, an antidepressant with unknown mechanisms of action. This work represents the first proof-of-concept study of a molecular classification of psychoactive drugs.
    Full-text · Article · Sep 2013 · BMC Genomics
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    • "The clustering of several component risk factors, described as the cardiometabolic syndrome, is observed in persons with SCI, including central obesity (Chen et al., 2006; Liang et al., 2007; Groah et al., 2009; Wahman et al., 2011), dyslipidemia (Brenes et al., 1986; Bauman et al., 1992; Maki et al., 1995), hypertension (in persons with paraplegia) (Nash and Mendez, 2007; Wahman et al., 2011), and either impaired fasting glucose or frank diabetes (Bauman and Spungen, 2001; Wahman et al., 2011). Adipose-derived peptide hormones, described as adipokines, contribute to both central and peripheral neuroendocrine regulation of energy metabolism (Ahima et al., 2006a, 2006b), and pathological dysregulation of their gene products and signal integration contribute to pro-inflammatory responses and metabolic dysfunction (Ouchi et al., 2011) associated with cardiometabolic risk (Deng and Scherer, 2010). Specifically, the adipokine leptin has been shown to play an integral role in regulating hypothalamic function (Zhang et al., 1994; Yu et al., 1997; Mantzoros, 1999) and obesity-linked metabolic and vascular diseases (Prins, 2002). "
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    ABSTRACT: Cardiovascular disease (CVD) represents a leading cause of mortality in chronic spinal cord injury (SCI). Several component risk factors are observed in SCI, however the underlying mechanisms that contribute to these risks have not been defined. Central and peripheral chronic inflammation is associated with metabolic dysfunction and CVD, including adipokine regulation of neuroendocrine and cardiac function and inflammatory processes initiated by the innate immune response. We use female C57 Bl/6 mice to examine neuroendocrine, cardiac, adipose and pancreatic signaling related to inflammation and metabolic dysfunction in response to experimentally induced chronic SCI. Using immuno-histochemical, -precipitation, and -blotting analysis, we show decreased proopiomelanocortin (POMC) and increased neuropeptide-Y (NPY) expression in the hypothalamic arcuate nucleus (ARC) and paraventricular nucleus (PVN), 1-month post-SCI. Long form leptin receptor (Ob-Rb), jak2/stat3/p38 and RhoA/ROCK signaling is significantly increased in heart tissue post-SCI, and we observe the formation and activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in visceral adipose tissue (VAT) and pancreas post-SCI. These data demonstrate neuroendocrine signaling peptide alterations, associated with central inflammation and metabolic dysfunction post-SCI, and provide evidence for the peripheral activation of signaling mechanisms involved in cardiac, VAT and pancreatic inflammation and metabolic dysfunction post-SCI. Further understanding of biological mechanisms contributing to SCI-related inflammatory processes and metabolic dysfunction associated with CVD pathology may help to direct therapeutic and rehabilitation countermeasures.
    Full-text · Article · Aug 2013 · ASN Neuro
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