SOCS2 Inhibits Mitochondrial Fatty Acid Oxidation via Suppressing LepR/JAK2/AMPK Signaling Pathway in Mouse Adipocytes

Suppressor of cytokine signaling 2 (SOCS2) plays an important role in fat deposition, skeletal muscle, central nervous system development, and mitochondria biogenesis. Nevertheless, the regulatory mechanisms of SOCS2 on mitochondrial fatty acid oxidation (FAO) remain unclear. Leptin could inhibit food intake and increase thermogenesis through leptin receptor (LepR), which was present in the hypothalamus and certain peripheral organs, including adipose tissue. With strong interest, we focused on the connection between leptin and SOCS2 and their effect on FAO in adipocytes. In our study, we found that the mRNA level of SOCS2 and the protein levels of PGC-1α, CPT-1b, FAT, and p-ACC were elevated by leptin in the inguinal adipose tissue of mice. On the contrary, the protein levels of FABP4, FATP1, and FAS were declined. The genes related to fatty acid oxidation such as PGC-1α, NRF-1, TFAM, CPT-1b, AOX1, COX2, and UCP2 were attenuated by SOCS2, but elevated by leptin. Moreover, fatty acid oxidation enzyme MCAD, LCAD, and Cyt C levels were reduced in response to SOCS2. These reductions correspond well with the reduced release of free fatty acid and the reduction of mitochondrial complexes I and III by SOCS2. Furthermore, JAK2/AMPK pathway-specific inhibitors could block the mitochondrial FAO; hence, this pathway was implied to have a potential impact on FAO. Together, these studies suggested that SOCS2 had a negative effect on mitochondrial fatty acid oxidation, and the LepR/JAK2/AMPK pathway played a crucial role in this process.

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Enhancing hepatic mitochondrial fatty acid oxidation stimulates eating in food-deprived mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00279.2014 ◽

2015 ◽

Vol 308 (2) ◽

pp. R131-R137 ◽

Cited By ~ 2

Author(s):

Abdelhak Mansouri ◽

Gustavo Pacheco-López ◽

Deepti Ramachandran ◽

Myrtha Arnold ◽

Claudia Leitner ◽

...

Keyword(s):

Fatty Acid ◽

Food Intake ◽

Fatty Acid Oxidation ◽

Food Deprivation ◽

Acid Oxidation ◽

Mitochondrial Fatty Acid Oxidation ◽

Protein Levels ◽

Malonyl Coa ◽

Mitochondrial Fatty Acid ◽

Hepatic Fatty Acid Oxidation

Hepatic fatty acid oxidation (FAO) has long been implicated in the control of eating. Nevertheless, direct evidence for a causal relationship between changes in hepatic FAO and changes in food intake is still missing. Here we tested whether increasing hepatic FAO via adenovirus-mediated expression of a mutated form of the key regulatory enzyme of mitochondrial FAO carnitine palmitoyltransferase 1A (CPT1mt), which is active but insensitive to inhibition by malonyl-CoA, affects eating and metabolism in mice. CPT1mt expression increased hepatocellular CPT1 protein levels. This resulted in an increase in circulating ketone body levels in fasted CPT1mt-expressing mice, suggesting an increase in hepatic FAO. These mice did not show any significant changes in cumulative food intake, energy expenditure, or respiratory quotient after 4-h food deprivation. After 24-h food deprivation, however, the CPT1mt-expressing mice displayed increased food intake. Thus expression of CPT1mt in the liver increases hepatic FAO capacity, but does not inhibit eating. Rather, it may even stimulate eating after prolonged food deprivation. These data do not support the hypothesis that an increase in hepatic FAO decreases food intake.

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