Peripheral Neuropathy and Hindlimb Paralysis in a Mouse Model of Adipocyte-Specific Knockout of Lkb1

Abstract

Brown adipose tissues (BAT) burn lipids to generate heat through uncoupled respiration, thus representing a powerful target to counteract lipid accumulation and obesity. The tumor suppressor liver kinase b1 (Lkb1) is a key regulator of cellular energy metabolism; and adipocyte-specific knockout of Lkb1 (Ad-Lkb1 KO) leads to the expansion of BAT, improvements in systemic metabolism and resistance to obesity in young mice. Here we report the unexpected finding that the Ad-Lkb1 KO mice develop hindlimb paralysis at mid-age. Gene expression analyses indicate that Lkb1 KO upregulates the expression of inflammatory cytokines in interscapular BAT and epineurial brown adipocytes surrounding the sciatic nerve. This is followed by peripheral neuropathy characterized by infiltration of macrophages into the sciatic nerve, axon degeneration, reduced nerve conductance, and hindlimb paralysis. Mechanistically, Lkb1 KO reduces AMPK phosphorylation and amplifies mammalian target-of-rapamycin (mTOR)-dependent inflammatory signaling specifically in BAT but not WAT. Importantly, pharmacological or genetic inhibition of mTOR ameliorates inflammation and prevents paralysis. These results demonstrate that BAT inflammation is linked to peripheral neuropathy.

BAT Expansion: A Panacea against Obesity? Lessons from LKB1

“…Overall, these results suggest that inhibition of LKB1 in adipocytes could be an interesting strategy to increase energy expenditure in the context of obesity. However, a deeper analysis of this mouse model, as reported in this issue of EBioMedicine , reveals that knocking down LKB1 in adipocytes induces late-onset expression of inflammatory cytokines in interscapular BAT (but not WAT) and epineurial brown adipocytes, eliciting macrophage infiltration in sciatic nerves ( Xiong et al, 2017 ). This process, that occurs through decreased AMPK phosphorylation and activation of mechanistic target of rapamycin (mTOR) pathway, leads to peripheral neuropathy characterized by abnormal axon morphology, axon degeneration, reduced nerve conductance and hindlimb paralysis, starting at the age of 8 months (See.…”

“…In this issue of EBioMedicine , Shihuan Kuang and colleagues move our biomedical understanding on the adverse effects of BAT development by using a mouse model with deletion of the serine/threonine kinase 11 (STK11), commonly known as liver kinase B1 (LKB1), specifically in adipocytes ( Xiong et al, 2017 ). LKB1 plays important roles in various biological processes including cellular energy metabolism, where it acts as the main upstream activating kinase of AMP-activated protein kinase (AMPK) ( López et al, 2016 ).…”

“…1 ). Notably, pharmacological or genetic inhibition of mTOR ameliorates inflammation and prevents paralysis ( Xiong et al, 2017 ).

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A Larger BAT Improves Metabolism but Whiffs on Safety

“…However, the possible deleterious effects of increasing BAT are not well understood. In EBioMedicine , Xiong et al highlight one such example ( Xiong et al, 2017 ). These authors investigated a mutant mouse ( Ad-Lkb1 ) harboring an adipocyte-specific knock out of the tumor suppressor liver kinase B1 (LKB1), which is also a key regulator of lipid metabolism.…”

“…Lkb1 was depleted in both WAT and BAT, but proinflammatory cytokines were only observed in BAT, with resulting inflammation in epineurial brown adipocytes around the sciatic nerve and subsequent damage. The neuropathy and inflammation were reduced by inhibiting mTOR genetically (via knock out) or pharmacologically (through treatment with rapamycin) ( Xiong et al, 2017 ). Importantly, suppressing inflammation is not risk-free, since adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling ( Asterholm et al, 2014 ).…”