A critical lipoprotein receptor reduces metabolic disorders brought on by low testosterone

Mouse in Kypreos lab
A mouse from the Kypreos laboratory study about the role of the low-density lipoprotein receptor in modulating testosterone’s effects.

Testosterone is the male sex hormone involved in sex differentiation, libido and erectile function. It’s also known to play a role in metabolism and influence obesity, type 2 diabetes and other metabolic disorders. But how testosterone participates in various metabolic pathways is not clear. In a paper just published in the Journal of Lipid Research, investigators demonstrate that the effects of testosterone on metabolism may be altered by the low-density lipoprotein receptor, a critical protein for the transport of lipid-modified proteins and the regulation of blood cholesterol levels.
 
The study is important, says lead author Kyriakos Kypreos at University of Patras Medical School in Greece, because it reveals “a novel role of the LDL receptor as a switch for processes associated with testosterone-induced metabolic alterations, such as body weight and body fat content, energy metabolism, and glucose tolerance.” Based on this finding, Kypreos adds that scientists can now focus on drugs to treat metabolic disorders that modulate the number of functional LDL receptors on cells.
 
Kypreos and colleagues have a longstanding interest in metabolic disorders in which testosterone is involved. Testosterone deficiency in men, called hypogonadism, is considered a primary risk factor for a number of disorders. These disorders include obesity, insulin resistance, and dyslipidemia, a condition where LDL-cholesterol and total cholesterol levels in blood are raised.

Kyriakos Kypreos
Kypreos

Kypreos says he and his colleagues came across research that suggested that the LDL receptor was an important receptor in diet-induced obesity. There is also research that shows that mutations in LDL receptor cause coronary heart disease and dyslipidemia.
 
Putting it all together, Kypreos and colleagues decided to investigate the potential involvement of the LDL receptor superfamily in the metabolic actions of testosterone. The investigators used genetically engineered male mice that were missing the LDL receptor. They surgically castrated these mice to see how low testosterone levels and a lack of LDL receptor affected metabolism. They fed the mice a high-fat diet “to mimic the human situation where obesity develops as a result of disruption of homeostasis between food intake and energy expenditure,” explains Kypreos.
 
The investigators discovered that the LDL receptor “is a main switch of testosterone actions on body metabolism,” says Kypreos. The receptor helps testosterone trigger those pathways involved in maintaining blood sugar and triglyceride levels. The investigators’ data also suggest that the receptor affects how testosterone activates fat burning in white adipose tissue. Kypreos says one of the group’s aims now is to search for “molecular targets for new pharmaceuticals that will promote fat burning through thermogenesis as a treatment of obesity and obesity-related complications.”

Rajendrani MukhopadhyayRajendrani Mukhopadhyay (rmukhopadhyay@asbmb.org) is the senior science writer and blogger for ASBMB. Follow her on Twitter (www.twitter.com/rajmukhop), and read her ASBMB Today blog, Wild Types.

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