Deletion of Lkb1 in adult mice results in body weight reduction and lethality

Shan, Tizhong; Xiong, Yan; Kuang, Shihuan

doi:10.1038/srep36561

Cited by 20 publications

(23 citation statements)

References 35 publications

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“…In seeking to account for this, we speculated that a defect in metabolism was a likely source of the growth retardation in the mice. To examine this possibility, we chose to focus on the AMPK-signaling pathway, because it has previously been reported that disruption of LKB1-AMPK-mTOR signaling results in a reduction in mouse body weight, analogous to our observations (14,15). The decreased body weight in the mutant animals corresponded with a reduction in food intake by the animals (Fig.…”

Section: Nischarin Lrr-deletion Improves Energy Balance Glucose and Isupporting

confidence: 66%

Nischarin inhibition alters energy metabolism by activating AMP-activated protein kinase

Dong¹,

Baranwal

García

et al. 2017

Journal of Biological Chemistry

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Nischarin (Nisch) is a key protein functioning as a molecular scaffold and thereby hosting interactions with several protein partners. To explore the physiological importance of Nisch, here we generated Nisch loss-of-function mutant mice and analyzed their metabolic phenotype. Nisch-mutant embryos exhibited delayed development, characterized by small size and attenuated weight gain. We uncovered the reason for this phenotype by showing that Nisch binds to and inhibits the activity of AMP-activated protein kinase (AMPK), which regulates energy homeostasis by suppressing anabolic and activating catabolic processes. The Nisch mutations enhanced AMPK activation and inhibited mechanistic target of rapamycin signaling in mouse embryonic fibroblasts as well as in muscle and liver tissues of mutant mice. Nisch-mutant mice also exhibited increased rates of glucose oxidation with increased energy expenditure, despite reduced overall food intake. Moreover, the Nisch-mutant mice had reduced expression of liver markers of gluconeogenesis associated with increased glucose tolerance. As a result, these mice displayed decreased growth and body weight. Taken together, our results indicate that Nisch is an important AMPK inhibitor and a critical regulator of energy homeostasis, including lipid and glucose metabolism.

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Section: Nischarin Lrr-deletion Improves Energy Balance Glucose and Isupporting

confidence: 66%

Nischarin inhibition alters energy metabolism by activating AMP-activated protein kinase

Dong¹,

Baranwal

García

et al. 2017

Journal of Biological Chemistry

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“…It has previously been shown that mice with systemic autophagy ablation have a life span of 2-3 months and the mortality is due to initial Streptococcus infection and eventual neurodegeneration (16). Whereas, adult mice with whole-body Lkb1 deletion survive for up to 6 weeks (23). Given that both Lkb1 signaling and autophagy pathway regulate cellular homeostasis (12,16,18,24), we hypothesize that upregulation of autophagy in Lkb1-deficient mice might compensate for the acute Lkb1 loss to maintain energy homeostasis for mouse survival.…”

Section: Interaction Of Lkb1 and Autophagy Is Required For Adult Mousmentioning

confidence: 99%

Autophagy Compensates for Lkb1 Loss to Maintain Adult Mice Homeostasis and Survival

Guo

Khayati

Bhatt

et al. 2020

Preprint

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Liver Kinase B1 (LKB1) is the major energy sensor for cells to respond to metabolic stress. Autophagy degrades and recycles proteins, macromolecules, and organelles for cells to survive starvation. To access the role and cross-talk between autophagy and Lkb1 in normal tissue homeostasis, we generated genetically engineered mouse models where we can conditionally delete Lkb1 and autophagy essential gene, Atg7, respectively or simultaneously, throughout the adult mice. We found that Lkb1 was essential for the survival of adult mice, and autophagy activation could temporarily compensate for the acute loss of Lkb1 and extend mouse life span. We further found that acute deletion of Lkb1 in adult mice led to impaired intestinal barrier function, hypoglycemia, and abnormal serum metabolism, which was partly rescued by the Lkb1 loss-induced autophagy upregulation via inhibiting p53 induction. Taken together, we demonstrated that autophagy and Lkb1 work synergistically to maintain adult mouse homeostasis and survival.

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“…AMPK is a conserved serine/threonine kinase that functions in the regulation of energy metabolism [16]. A previous study showed that LKB1 is necessary for white adipose tissue (WAT) growth and differentiation [17]. Moreover, the LKB1/AMPK signaling pathway negatively regulates WAT [18].…”

Section: Introductionmentioning

confidence: 99%

Intraventricular Injection of LKB1 Inhibits the Formation of Diet-Induced Obesity in Rats by Activating the AMPK-POMC Neurons-Sympathetic Nervous System Axis

Liang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Obesity is increasingly becoming a major public health problem worldwide. Peripheral LKB1 inhibits white fat generation, but the effect of central LKB1 on diet-induced obesity (DIO) is unknown. Therefore, we examined whether LKB1 over-expression in the hypothalamus can inhibit the development of obesity. Methods: Adult male Sprague-Dawley rats were anesthetized and placed in a stereotaxic apparatus. LKB1-AAV-EGFP (2.0 × 10⁸ or 2.0 × 10¹⁰ vector genomes) or Control-AAV-EGFP (2.0 × 10⁸ vector genomes) was injected into the third ventricle. After administration, the rats were fed a high-fat diet (HFD) for 9 weeks to induce obesity. Rats fed a chow fat diet were used as normal controls. Results: LKB1 delivery decreased body weight, energy intake, fat mass, and serum lipid levels. LKB1 also improved HFD-induced hepatic fatty degeneration. Interestingly, LKB1 over-expression in the hypothalamus activated the AMPK-POMC neurons-sympathetic nervous system (SNS) axis, which can release epinephrine to promote white fat browning. Conversely, the elevated expression of MC3R/MC4R inhibited food intake. These two factors worked together to inhibit the development of obesity. Conclusions: LKB1 in the hypothalamus may have therapeutic potential for DIO through the activation of the AMPK-POMC neurons-SNS axis.

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Deletion of Lkb1 in adult mice results in body weight reduction and lethality

Cited by 20 publications

References 35 publications

Nischarin inhibition alters energy metabolism by activating AMP-activated protein kinase

Nischarin inhibition alters energy metabolism by activating AMP-activated protein kinase

Autophagy Compensates for Lkb1 Loss to Maintain Adult Mice Homeostasis and Survival

Intraventricular Injection of LKB1 Inhibits the Formation of Diet-Induced Obesity in Rats by Activating the AMPK-POMC Neurons-Sympathetic Nervous System Axis

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