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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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Current Issue

ACAA1 knockout increases the survival rate of KPC mice by activating autophagy

Ho Lee, Mingyu Kang, Sung Hoon Sim, Joon Hee Kang, ... Soo-Youl Kim

ACAA1 knockout increases the survival rate of KPC mice by activating autophagy

 

Objectives

We found that the levels of the peroxisomal fatty acid oxidation (FAO) marker in pancreatic ductal adenocarcinoma (PDAC) patients were higher than those in healthy individuals, based on tissue microarray analysis. This study investigates FAO in preclinical in vitro and in vivo models.

Methods

To examine the role of FAO in the peroxisome, we created acetyl-coenzyme A acyltransferase (ACAA1) knockout mice, crossed them with KPC mice, and monitored their survival rates. Additionally, we tested a mouse xenograft model with ACAA1 knockdown in human PDAC cells.

Results

In normal cells, ACAA1 knockdown did not affect oxygen consumption. In contrast, in PDAC cells, ACAA1 knockdown reduced the oxygen consumption rate by up to 60% and decreased ATP production by up to 70%. This suggests that peroxisomes in PDAC supply various acyl-carnitines for FAO in mitochondria. In PDAC cells, ACAA1 knockdown lowered ATP levels, resulting in mTOR inactivation and autophagy induction. Additionally, ACAA1 knockdown significantly increased LC3-II levels, leading to growth retardation in mouse xenograft models. Acaa1a+/− mice showed a median survival increase of 3 weeks after crossing Acaa1a+/− with KPC mice (KrasG12D/+; Trp53R172H/+; Pdx1-Cre, a genetically engineered mice model for PDAC).

Conclusions

ACAA1 knockdown inhibited tumor growth by triggering autophagy, which supported the survival of KPC mice. The most important benefit of targeting ACAA1 is that it blocks tumor growth specifically in cancer cells without harming normal cell energy metabolism.

 

 

Articles in Press

ACAA1 knockout increases the survival rate of KPC mice by activating autophagy

Ho Lee, Mingyu Kang, Sung Hoon Sim, Joon Hee Kang, ... Soo-Youl Kim

ACAA1 knockout increases the survival rate of KPC mice by activating autophagy

 

Objectives

We found that the levels of the peroxisomal fatty acid oxidation (FAO) marker in pancreatic ductal adenocarcinoma (PDAC) patients were higher than those in healthy individuals, based on tissue microarray analysis. This study investigates FAO in preclinical in vitro and in vivo models.

Methods

To examine the role of FAO in the peroxisome, we created acetyl-coenzyme A acyltransferase (ACAA1) knockout mice, crossed them with KPC mice, and monitored their survival rates. Additionally, we tested a mouse xenograft model with ACAA1 knockdown in human PDAC cells.

Results

In normal cells, ACAA1 knockdown did not affect oxygen consumption. In contrast, in PDAC cells, ACAA1 knockdown reduced the oxygen consumption rate by up to 60% and decreased ATP production by up to 70%. This suggests that peroxisomes in PDAC supply various acyl-carnitines for FAO in mitochondria. In PDAC cells, ACAA1 knockdown lowered ATP levels, resulting in mTOR inactivation and autophagy induction. Additionally, ACAA1 knockdown significantly increased LC3-II levels, leading to growth retardation in mouse xenograft models. Acaa1a+/− mice showed a median survival increase of 3 weeks after crossing Acaa1a+/− with KPC mice (KrasG12D/+; Trp53R172H/+; Pdx1-Cre, a genetically engineered mice model for PDAC).

Conclusions

ACAA1 knockdown inhibited tumor growth by triggering autophagy, which supported the survival of KPC mice. The most important benefit of targeting ACAA1 is that it blocks tumor growth specifically in cancer cells without harming normal cell energy metabolism.

 

 

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13th
Helmholtz Diabetes Conference 
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