Dataset Information

SF1-Specific AMPKα1 Deletion Protects Against Diet-Induced Obesity.

ABSTRACT: AMPK is a cellular gauge that is activated under conditions of low energy, increasing energy production and reducing energy waste. Current evidence links hypothalamic AMPK with the central regulation of energy balance. However, it is unclear whether targeting hypothalamic AMPK has beneficial effects in obesity. Here, we show that genetic inhibition of AMPK in the ventromedial nucleus of the hypothalamus (VMH) protects against high-fat diet (HFD)-induced obesity by increasing brown adipose tissue (BAT) thermogenesis and subsequently energy expenditure. Notably, this effect depends upon the AMPKα1 isoform in steroidogenic factor 1 (SF1) neurons of the VMH, since mice bearing selective ablation of AMPKα1 in SF1 neurons display resistance to diet-induced obesity, increased BAT thermogenesis, browning of white adipose tissue, and improved glucose and lipid homeostasis. Overall, our findings point to hypothalamic AMPK in specific neuronal populations as a potential druggable target for the treatment of obesity and associated metabolic disorders.

SUBMITTER: Seoane-Collazo P

PROVIDER: S-EPMC6198345 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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SF1-Specific AMPKα1 Deletion Protects Against Diet-Induced Obesity.

Seoane-Collazo Patricia P Roa Juan J Rial-Pensado Eva E Liñares-Pose Laura L Beiroa Daniel D Ruíz-Pino Francisco F López-González Tania T Morgan Donald A DA Pardavila José Ángel JÁ Sánchez-Tapia María Jesús MJ Martínez-Sánchez Noelia N Contreras Cristina C Fidalgo Miguel M Diéguez Carlos C Coppari Roberto R Rahmouni Kamal K Nogueiras Rubén R Tena-Sempere Manuel M López Miguel M

Diabetes 20180813 11

AMPK is a cellular gauge that is activated under conditions of low energy, increasing energy production and reducing energy waste. Current evidence links hypothalamic AMPK with the central regulation of energy balance. However, it is unclear whether targeting hypothalamic AMPK has beneficial effects in obesity. Here, we show that genetic inhibition of AMPK in the ventromedial nucleus of the hypothalamus (VMH) protects against high-fat diet (HFD)-induced obesity by increasing brown adipose tissue ...[more]

PMID: 30104247

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Project description:ABSTRACT OBJECTIVE: Genome Wide Association Studies (GWAS) in humans, dogs, and livestock have uncovered genes which may play a role in metabolism. However, functional analysis is required to link the metabolic phenotype with the associated gene. Here we identified the Ligand Dependent Corepressor-Like (LCoRL) as a potential metabolic regulator. METHOD: We used CRISPR/Cas9 approaches in mice to generate a Lcorl null allele (Lcorl-/-). We characterized Lcorl-/- mice by assessing body weight, body composition, food intake, and glucose homeostasis as well as assessing transcriptional changes in Lcorl-/- livers by RNA-sequencing. Finally, we challenged mice with a 60% high fat diet (HFD) and a treadmill exercise stress test. RESULTS: Mice homozygous for loss of Lcorl are viable and fertile. However, Lcorl-/- pups show stunted postnatal growth for the first few weeks of life. This is followed by a catchup growth, such that, Lcorl-/- mice are indistinguishable from wildtype littermates by 7-9 weeks of age. Three-week-old mice show reduced circulating insulin like growth factor-1 (IGF-1) levels without a change in pituitary Growth hormone (Gh) mRNA levels. Interestingly, Lcorl-/- mice remain lean compared to wildtype littermates as they age. This is associated with a decrease in daily food intake. Additionally, Lcorl-/- mice show no change in energy expenditure; however, Lcorl-/- mice show a greater amplitude of their respiratory exchange ratio (RER) compared to controls, suggesting differential usage of fat and carbohydrates across the light/dark cycle. This altered RER may result from the reduction in day-time food intake or disrupted mobilization of fat and carbohydrate stores. Consistent with enhanced metabolic health, Lcorl-/- mice also show improved glucose tolerance and insulin sensitivity. Finally, Lcorl-/- mice are protected against a 60% high fat diet challenge and show reduced exercise capacity in a stress test. CONCLUSION: This phenotypic characterization of the Lcorl-/- mouse reveals that LCoRL is a causal gene resulting in the changes in metabolism seen in GWAS in humans and livestock and provides novel mechanistic insights of a gene important in human disease and economically valuable traits in livestock.

Project description:BackgroundEcto-nucleoside triphosphate diphosphohydrolase 3 (NTPDase3), also known as CD39L3, is the dominant ectonucleotidase expressed by beta cells in the islet of Langerhans and on nerves. NTPDase3 catalyzes the conversion of extracellular ATP and ADP to AMP and modulates purinergic signaling. Previous studies have shown that NTPDase3 decreases insulin release from beta-cells in vitro. This study aims to determine the impact of NTPDase3 in diet-induced obesity (DIO) and metabolism in vivo.MethodsWe developed global NTPDase3 deficient (Entpd3-/-) and islet beta-cell-specific NTPDase-3 deficient mice (Entpd3flox/flox,InsCre) using Ins1-Cre targeted gene editing to compare metabolic phenotypes with wildtype (WT) mice on a high-fat diet (HFD).ResultsEntpd3-/- mice exhibited similar growth rates compared to WT on chow diet. When fed HFD, Entpd3-/- mice demonstrated significant resistance to DIO. Entpd3-/- mice consumed more calories daily and exhibited less fecal calorie loss. Although Entpd3-/- mice had no increases in locomotor activity, the mice exhibited a significant increase in basal metabolic rate when on the HFD. This beneficial phenotype was associated with improved glucose tolerance, but not higher insulin secretion. In fact, Entpd3flox/flox,InsCre mice demonstrated similar metabolic phenotypes and insulin secretion compared to matched controls, suggesting that the expression of NTPDase3 in beta-cells was not the primary protective factor. Instead, we observed a higher expression of uncoupling protein 1 (UCP-1) in brown adipose tissue and an augmented browning in inguinal white adipose tissue with upregulation of UCP-1 and related genes involved in thermogenesis in Entpd3-/- mice.ConclusionsGlobal NTPDase3 deletion in mice is associated with resistance to DIO and obesity-associated glucose intolerance. This outcome is not driven by the expression of NTPDase3 in pancreatic beta-cells, but rather likely mediated through metabolic changes in adipocytes.

Dataset Information

SF1-Specific AMPKα1 Deletion Protects Against Diet-Induced Obesity.

Publications

SF1-Specific AMPKα1 Deletion Protects Against Diet-Induced Obesity.

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