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Brown adipose tissue (BAT) is a specialized fat tissue that is rich in mitochondria and promotes non-shivering thermogenesis by expressing the uncoupling protein 1 (UCP1). Unlike white adipose tissue, it burns calories to produce heat and therefore plays a key role in energy regulation and controlling metabolic health. Increasing energy expenditure by BAT activation is an intriguing therapeutic approach to combat the overwhelming obesity pandemic, either alone or to complement the current pharmacotherapy that mainly addresses energy intake based on the incretin-mimetic poly-agonist class of drugs. With this in mind it is not surprising that a lot of research was conducted to understand the molecular underpinnings of BAT regulation specifically addressing environmental cues. Cold exposure is the most powerful inducer of BAT activation leading to the upregulation of thermogenic gene program and adrenergic receptor-mediated activation of lipolysis and metabolism. BAT activation also occurs post-prandially, especially after acute overfeeding, to trigger diet-induced thermogenesis. However, this compensatory component of energy-expenditure is impaired during chronic overfeeding, a phenomenon that was termed adaptive thermogenesis, and is believed to further drive weight gain and obesity.

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Leupaxin promotes hepatic gluconeogenesis and glucose metabolism by coactivation with hepatic nuclear factor 4α

Xiaomin Luo, Fang Liu, Lijun Zhu, Caizhi Liu, ... Zhijian Zhang

Leupaxin promotes hepatic gluconeogenesis and glucose metabolism by coactivation with hepatic nuclear factor 4α

 

Background

As the primary source of glucose during fasting, hepatic gluconeogenesis is rigorously regulated to maintain euglycemia. Abnormal gluconeogenesis in the liver can lead to hyperglycemia, a key diagnostic marker and the primary pathological contributor to type 2 diabetes (T2D) and metabolic disorders. Hepatic nuclear factor-4 (HNF4α) is an important regulator of gluconeogenesis. In this study, we identify leupaxin (LPXN) as a novel coactivator for HNF4α. Although previous studies have shown that LPXN is highly correlated with cancer types such as B-cell differentiation and hepatocellular carcinoma progression, the role of LPXN in gluconeogenesis remains unknown.

Methods

We initially used protein pull-down assays, mass spectrometry and luciferase assays to identify the coactivator that interacts with HNF4α in gluconeogenesis. We further leveraged cell cultures and mouse models to validate the functional importance of molecular pathway during gluconeogenesis by using adenovirus-mediated overexpression and adeno-associated virus shRNA–mediated knockdown both in vivo and ex vivo, such as in ob/db/DIO mice, HepG2 and primary hepatocytes. Following, we used CUT&Tag and chip qPCR to identify the LPXN-mediated mechanisms underlying the observed abnormal gluconeogenesis. Additionally, we assessed the translational relevance of our findings using human liver tissues from both healthy donors and patients with obesity/type 2 diabetes.

Results

We found that LPXN interacts with HNF4α to participate in gluconeogenesis. Knockdown of LPXN expression in the liver effectively enhanced glucose metabolism, while its overexpression in the liver effectively inhibited it. Mechanistically, LPXN could translocate into the nucleus and was essential for regulating gluconeogenesis by binding to the PEPCK promoter, which controlled the expression of an enzyme involved in gluconeogenesis, mainly through the Gcg-cAMP-PKA pathway. Additionally, LPXN expression was found to be increased in the livers of patients with steatosis and diabetes, supporting a pathological role of LPXN.

Conclusions

Taken together, our study provides evidence that LPXN plays a critical role in modulating hepatic gluconeogenesis, thereby reinforcing the fact that targeting LPXN may be a potential approach for the treatment of diabetes and metabolic disorders.

 

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Articles in Press

Leupaxin promotes hepatic gluconeogenesis and glucose metabolism by coactivation with hepatic nuclear factor 4α

Xiaomin Luo, Fang Liu, Lijun Zhu, Caizhi Liu, ... Zhijian Zhang

Leupaxin promotes hepatic gluconeogenesis and glucose metabolism by coactivation with hepatic nuclear factor 4α

 

Background

As the primary source of glucose during fasting, hepatic gluconeogenesis is rigorously regulated to maintain euglycemia. Abnormal gluconeogenesis in the liver can lead to hyperglycemia, a key diagnostic marker and the primary pathological contributor to type 2 diabetes (T2D) and metabolic disorders. Hepatic nuclear factor-4 (HNF4α) is an important regulator of gluconeogenesis. In this study, we identify leupaxin (LPXN) as a novel coactivator for HNF4α. Although previous studies have shown that LPXN is highly correlated with cancer types such as B-cell differentiation and hepatocellular carcinoma progression, the role of LPXN in gluconeogenesis remains unknown.

Methods

We initially used protein pull-down assays, mass spectrometry and luciferase assays to identify the coactivator that interacts with HNF4α in gluconeogenesis. We further leveraged cell cultures and mouse models to validate the functional importance of molecular pathway during gluconeogenesis by using adenovirus-mediated overexpression and adeno-associated virus shRNA–mediated knockdown both in vivo and ex vivo, such as in ob/db/DIO mice, HepG2 and primary hepatocytes. Following, we used CUT&Tag and chip qPCR to identify the LPXN-mediated mechanisms underlying the observed abnormal gluconeogenesis. Additionally, we assessed the translational relevance of our findings using human liver tissues from both healthy donors and patients with obesity/type 2 diabetes.

Results

We found that LPXN interacts with HNF4α to participate in gluconeogenesis. Knockdown of LPXN expression in the liver effectively enhanced glucose metabolism, while its overexpression in the liver effectively inhibited it. Mechanistically, LPXN could translocate into the nucleus and was essential for regulating gluconeogenesis by binding to the PEPCK promoter, which controlled the expression of an enzyme involved in gluconeogenesis, mainly through the Gcg-cAMP-PKA pathway. Additionally, LPXN expression was found to be increased in the livers of patients with steatosis and diabetes, supporting a pathological role of LPXN.

Conclusions

Taken together, our study provides evidence that LPXN plays a critical role in modulating hepatic gluconeogenesis, thereby reinforcing the fact that targeting LPXN may be a potential approach for the treatment of diabetes and metabolic disorders.

 

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SAVE THE DATE!

13th
Helmholtz Diabetes Conference 
Munich, 21-23. Sep 2026                                                                                                                             

2024 impact factor: 6.6

You are what you eat

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