Rodent obesity models: An overview

Tschöp, Matthias H.; Heiman, Mark L.

doi:10.1055/s-2001-17297

Cited by 190 publications

(144 citation statements)

References 74 publications

(83 reference statements)

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“…ApoE mRNA levels are reduced in the hypothalamus of genetically obese (ob/ob) mice and rats with HFdiet-induced obesity. ob/ob mice are a well-known animal model for obesity (18). Using qPCR, we found that apoE mRNA levels are significantly reduced in the hypothalami of ob/ob mice compared with those in lean control animals (P Ͻ 0.05, Fig.…”

Section: Resultsmentioning

confidence: 86%

Brain Apolipoprotein E: an Important Regulator of Food Intake in Rats

et al. 2008

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OBJECTIVE-The worldwide prevalence of obesity is increasing at an alarming rate, along with the associated increased rates of type 2 diabetes, heart disease, and some cancers. While efforts to address environmental factors responsible for the recent epidemic must continue, investigation into the anorectic functions of potential molecules we present here, such as apolipoprotein (apo)E, offers exciting possibilities for future development of successful anti-obesity therapies.RESEARCH DESIGN AND METHODS-Changes in feeding behavior after intracerebroventricular injection of apoE, the regulation of hypothalamic apoE gene expression by energy status, and the interaction of hypothalamic apoE with other neuropeptides were studied.RESULTS-Intracerebroventricular apoE significantly decreased food intake without causing malaise, whereas intracerebroventricular infusion of apoE antiserum stimulated feeding, implying that endogenous apoE tonically inhibits food intake. Consistent with this, apoE was present in the hypothalamus, a brain site intimately involved in the integration of signals for energy homeostasis. Fasted rats exhibited significantly decreased apoE gene expression in the hypothalamus, and refeeding of these rats for 4 h evoked a significant increase of hypothalamic apoE mRNA levels. Both genetically obese (ob/ob) mice and rats with high-fat diet-induced obesity had significantly reduced hypothalamic apoE mRNA levels compared with their lean control counterparts, suggesting that decreased apoE may contribute to hyperphagia in these obese animals. Additionally, apoE-stimulated hypothalamic proopiomelanocortin gene expression and SHU9119, a melanocortin 3/4 receptor antagonist, attenuated the inhibitory function of apoE on feeding.CONCLUSIONS-These data demonstrate that apoE suppresses food intake via a mechanism enhancing melanocortin signaling in the hypothalamus. Diabetes 57:2092-2098, 2008 E levated body weight resulting in obesity is a major health problem in the U.S. and is associated with significant morbidity and mortality from coronary heart disease, type 2 diabetes, and other disorders. One well-established risk factor for becoming obese is food consumption in excess of energy expenditure. Evidence links a complex circuitry in the mediobasal hypothalamus with the control of food intake and energy expenditure. Obese animals have a blunted response to satiation signals such as leptin and insulin, raising the possibility that defective satiation signaling within the central nervous system and/or peripheral tissues may contribute to the etiology of obesity.Apolipoprotein (apo)E, a 34,000-kDa glycoprotein involved in lipid metabolism (1), is predominantly produced in the liver and brain (2). Recent data suggest that apoE plays additional roles in the brain, regulating both neuronal and astrocyte functions, including preventing excitotoxicity (3), promoting neuron survival and sprouting (4), protecting neurons against oxidative stress (5), and regulating innate and adaptive immune responses (6). We here descr...

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Section: Resultsmentioning

confidence: 86%

Brain Apolipoprotein E: an Important Regulator of Food Intake in Rats

et al. 2008

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“…The system is acknowledged to have an important function in regulation of satiety and energy expenditure (Yaswen et al 1999;Spiegelman & Flier 2001;Cheung et al 1997;Azzara et al 2002). MC4R knockout mice exhibit a well-described phenotype defined by increased lean body mass and fat mass, hyperphagia and disturbances in the metabolic response to overnutrition (Mountjoy et al 1994;Huszar et al 1997;Tschop & Heiman 2001). Furthermore, loss of MC4R function is the most frequent monogenetic alteration in severely obese humans (Krude et al 1998) and in severe, early onset childhood obesity the frequency of mutations in the MC4R locus is 4-6% (Farooqi et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Characterization of murine melanocortin receptors mediating adipocyte lipolysis and examination of signalling pathways involved

Møller

Raun

Jacobsen

et al. 2011

Molecular and Cellular Endocrinology

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The melanocortin receptors (MCRs) belong to the G-protein coupled receptors (family A). So far, 5 different subtypes have been described (MC1R-MC5R) and of these MC2R and MC5R have been proposed to act directly in adipocytes and regulate lipolysis in rodents. Using ACTH and -melanocyte stimulating hormone (-MSH) generated from proopiomelanocortin (POMC), as well as synthetic MSH-analogues to stimulate lipolysis in murine 3T3-L1 adipocytes it is shown that MC2R and MC5R are lipolytic mediators in differentiated 3T3-L1 adipocytes. Involvement of cAMP, phosphorylated extracellular signal-regulated kinase (ERK) 1/2, protein kinase B (PKB), adenosine 5' monophosphateactivated protein kinase (AMPK) and Jun-amino-terminal kinase (JNK) in MCR mediated lipolysis were studied. Interestingly, results obtained in 3T3-L1 cells suggest that lipolysis stimulated by -MSH, NDP--MSH, MT-II, SHU9119and PG-901 is mediated through MC5R in a cAMP independent manner. Finally, we identify essential differences in MCR mediated lipolysis when using 3T3-L1 cells compared to primary adipocytes. INTRODUCTIONThe melanocortin system acts through multiple pathways relevant for the prevention of obesity and obesity-related complications (Cone 1999;Marks et al. 2002;Spiegelman & Flier 2001). The system is acknowledged to have an important function in regulation of satiety and energy expenditure (Yaswen et al. 1999;Spiegelman & Flier 2001;Cheung et al. 1997;Azzara et al. 2002). MC4R knockout mice exhibit a well-described phenotype defined by increased lean body mass and fat mass, hyperphagia and disturbances in the metabolic response to overnutrition (Mountjoy et al. 1994;Huszar et al. 1997;Tschop & Heiman 2001). Furthermore, loss of MC4R function is the most frequent monogenetic alteration in severely obese humans (Krude et al. 1998) and in severe, early onset childhood obesity the frequency of mutations in the MC4R locus is 4-6% (Farooqi et al. 2003). Besides the effect on satiety and energy expenditure, the melanocortin system is believed to influence insulin release and insulin sensitivity (Fan et al. 2000;Huo et al. 2009). The melanocortin peptides and their receptors are also suspected to have a direct lipolytic effect on adipose tissues in rodents (Cho et al. 2005;Boston 1999;Spirovski et al. 1975). However this effect is controversial in humans (Hoch et al. 2007). The effect of melanocortins on adipocytes have by some researchers been explained by neuronal regulation of lipolysis (Brito et al. 2007), since MC4R mRNA has been identified in sympathetic neurons connected to white adipose tissue (WAT), indicating that central MC4R might stimulate lipid mobilization in the periphery (Song et al. 2005). However, studies in differentiated murine 3T3-L1 adipocytes suggest a direct lipolytic effect stimulated by melanocortin peptides ACTH and -MSH (Bradley et al. 2005;Cho et al. 2005), Page 3 of 24 A c c e p t e d M a n u s c r i p t 3 which supports the earlier identification of MC2R and MC5R mRNA in this cell line (Boston & Cone 1996). MC1R...

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“…Although the etiology of obesity is complex, several factors have been implicated in its development, especially hypercaloric intake 3 . In this context, a variety of experimental models of obesity exist, however, dietary-induced obesity is the most relevant experimental model regarding human obesity 4 .…”

Section: Introductionmentioning

confidence: 99%