Metabolic Pitfalls of CNS Cre-Based Technology

Harno, Erika; Cottrell, Elizabeth; White, Anne

doi:10.1016/j.cmet.2013.05.019

Cited by 183 publications

(172 citation statements)

References 64 publications

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“…It is key to point out that, in addition to mediating recombination of floxed alleles in POMC neurons of the hypothalamus, Pomc-Cre lines also mediate recombination in extra-hypothalamic POMC-neurons and in some non-POMC neurons in adults (27). This limitation is inherent to most developmental Cre lines presently used by most research groups (13,25,30). Thus, it is possible that the phenotype reported here could be related to unspecific recombination of the CAAGS Lox-stop-LoxDeptor allele.…”

Section: Discussionmentioning

confidence: 99%

DEPTOR in POMC neurons affects liver metabolism but is dispensable for the regulation of energy balance

Caron

Labbé

Mouchiroud

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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-We have recently demonstrated that specific overexpression of DEP-domain containing mTOR-interacting protein (DEPTOR) in the mediobasal hypothalamus (MBH) protects mice against high-fat diet-induced obesity, revealing DEPTOR as a significant contributor to energy balance regulation. On the basis of evidence that DEPTOR is expressed in the proopiomelanocortin (POMC) neurons of the MBH, the present study aimed to investigate whether these neurons mediate the metabolic effects of DEPTOR. Here, we report that specific DEPTOR overexpression in POMC neurons does not recapitulate any of the phenotypes observed when the protein was overexpressed in the MBH. Unlike the previous model, mice overexpressing DEPTOR only in POMC neurons 1) did not show differences in feeding behavior, 2) did not exhibit changes in locomotion activity and oxygen consumption, 3) did not show an improvement in systemic glucose metabolism, and 4) were not resistant to high-fat diet-induced obesity. These results support the idea that other neuronal populations are responsible for these phenotypes. Nonetheless, we observed a mild elevation in fasting blood glucose, insulin resistance, and alterations in liver glucose and lipid homeostasis in mice overexpressing DEP-TOR in POMC neurons. Taken together, these results show that DEPTOR overexpression in POMC neurons does not affect energy balance regulation but could modulate metabolism through a brainliver connection. DEPTOR; mTOR; POMC; energy balance; glucose metabolism THE CONTROL OF FOOD INTAKE and energy expenditure is ensured by neurons of several brain regions, including the mediobasal hypothalamus (MBH), which has emerged as a major center of integration for nutrient and hormonal cues (26,33). MBH hosts several neuronal populations, including the proopiomelanocortin (POMC) and neuropeptide Y (NPY)/agouti-related protein (AgRP)/GABA-producing neurons of the arcuate nucleus, as well as steroidogenic factor 1 (SF1) neurons of the ventromedial hypothalamus. Over the years, these neurons were shown to play critical roles in the regulation of systemic metabolic homeostasis (17, 21). Intensive efforts are currently being made to better understand the molecular mechanisms by which MBH neurons control energy balance and systemic metabolism (11, 15).The mechanistic target of rapamycin (mTOR) plays an important role in the hypothalamic regulation of energy balance and glucose homeostasis (3,8,9). mTOR is a serine/threonine kinase that nucleates two protein complexes named mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) (20). These complexes are part of a well-conserved anabolic pathway that modulates growth and metabolism in response to nutrients and growth factors. They include several proteins, including DEP-domain containing mTOR-interacting protein (DEPTOR), a component of both mTORC1 and mTORC2 (31). Recently, we have characterized the expression of Deptor in the rat and mouse brain and have shown that this gene is highly expressed in several structures involved in energy balance regulation, i...

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Section: Discussionmentioning

confidence: 99%

DEPTOR in POMC neurons affects liver metabolism but is dispensable for the regulation of energy balance

Caron

Labbé

Mouchiroud

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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“…This protective effect against HFD feeding was not observed in mice that were heterozygous for CNS-specific Tak1 deletion (Tak1 flox/+ NestinCre) (Fig. S3F), demonstrating that expression of Nestin-Cre alone did not cause observable effects under our experimental settings, although an earlier study reported a marginal reduction in weight gain upon Nestin-Cre expression (Harno et al, 2013). Thus, CNS-specific Tak1 deletion is the cause of resistance to HFD-induced excessive weight gain.…”

Section: Tak1 Deficiency Increases Er Volumementioning

confidence: 49%

TAK1 determines susceptibility to endoplasmic reticulum stress and leptin resistance in the hypothalamus

Sai

Morioka

Takaesu

et al. 2016

Journal of Cell Science

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Sustained endoplasmic reticulum (ER) stress disrupts normal cellular homeostasis and leads to the development of many types of human diseases, including metabolic disorders. TAK1 (also known as MAP3K7) is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family and is activated by a diverse set of inflammatory stimuli. Here, we demonstrate that TAK1 regulates ER stress and metabolic signaling through modulation of lipid biogenesis. We found that deletion of Tak1 increased ER volume and facilitated ER-stress tolerance in cultured cells, which was mediated by upregulation of sterol-regulatory-element-binding protein (SREBP)-dependent lipogenesis. In the in vivo setting, central nervous system (CNS)-specific Tak1 deletion upregulated SREBP-target lipogenic genes and blocked ER stress in the hypothalamus. Furthermore, CNS-specific Tak1 deletion prevented ER-stress-induced hypothalamic leptin resistance and hyperphagic obesity under a high-fat diet (HFD). Thus, TAK1 is a crucial regulator of ER stress in vivo, which could be a target for alleviation of ER stress and its associated disease conditions.

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“…The effect of the GLP-1 mimetic on islet cell composition is reproduced by the DPP4i, albeit at a slower pace indicating that beta cell ablation is correlated with the concentration of the incretin in the circulation. These observations add to previously raised concerns regarding the toxic effects of Cre on cell function (1,3,4,30) and highlight the need for caution in the interpretation of results using the Cre-lox technology.…”

Section: Discussionmentioning

confidence: 87%

“…It has been proposed that the physiological abnormalities of transgenic RIP-Cre mice may be avoided using an inducible form of Cre (1,3,4). Although the efficiency of recombination is lower than in lines with constitutive Cre expression, the possibility was raised that the appearance of metabolic abnormalities would be evaded with the lower levels of recombinase.…”

mentioning

confidence: 99%

Mouse Insulin Cells Expressing an Inducible RIPCre Transgene Are Functionally Impaired

Teitelman

Kedees

2015

Journal of Biological Chemistry

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Background:We tested whether insulin cells expressing an inducible RIP-Cre transgene display a normal phenotype. Results: RipCre insulin cells die when the stimulation of insulin synthesis is protracted. Conclusion: Beta cells expressing an inducible RIP-Cre transgene are functionally deficient. Significance: The use of an inducible RIPCre system to examine beta cell gene function/development could distort experimental results.

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Metabolic Pitfalls of CNS Cre-Based Technology

Cited by 183 publications

References 64 publications

DEPTOR in POMC neurons affects liver metabolism but is dispensable for the regulation of energy balance

DEPTOR in POMC neurons affects liver metabolism but is dispensable for the regulation of energy balance

TAK1 determines susceptibility to endoplasmic reticulum stress and leptin resistance in the hypothalamus

Mouse Insulin Cells Expressing an Inducible RIPCre Transgene Are Functionally Impaired

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