A PRDM16-driven signal regulates body composition in testosterone-treated hypogonadal men.

Testosterone therapy significantly increased serum testosterone and estradiol levels after 6 months of treatment.

• Single-arm, open-label clinical trial conducted between 2011 and 2016 involving 105 men aged 40-74 years with late-onset hypogonadism.
• Participants received intramuscular testosterone cypionate 200 mg every 2 weeks for 18 months.
• Serum testosterone and estradiol levels were significantly increased after 6 months of T therapy compared to baseline.
• The increase in estradiol is proposed as a key mediator of downstream molecular changes.

Testosterone therapy significantly reduced fat mass and increased lean mass after 6 months of treatment.

• Both total body fat mass and truncal fat mass were reduced after 6 months of T therapy.
• Lean mass was significantly increased after 6 months of T therapy compared to baseline.
• Body composition was assessed as part of the secondary analysis of specimens from the clinical trial.
• These changes in body composition were accompanied by corresponding molecular changes in adipogenic and myogenic markers.

Testosterone therapy significantly reduced expression of adipogenic markers PPARγ in subcutaneous fat and ADIPSIN in serum.

• PPARγ expression in subcutaneous fat (SCF) was significantly reduced after 6 months of T therapy compared to baseline.
• Serum ADIPSIN levels measured by ELISA were significantly reduced after 6 months of T therapy.
• Gene expression was measured by real-time quantitative PCR in SCF obtained from participants at baseline and 6 months.
• Reduction in these adipogenic markers is consistent with the observed decrease in fat mass.

Testosterone therapy significantly increased expression of myogenic markers MYOD in peripheral blood mononuclear cells and PAX7 and FOLLISTATIN in serum.

• MYOD expression in peripheral blood mononuclear cells (PBMC) was significantly increased after 6 months of T therapy compared to baseline.
• Serum PAX7 levels measured by ELISA were significantly increased after 6 months of T therapy.
• Serum FOLLISTATIN levels measured by ELISA were significantly increased after 6 months of T therapy.
• Gene expression in PBMC was measured by real-time quantitative PCR at baseline and 6 months.
• These increases in myogenic markers are consistent with the observed increase in lean mass.

PRDM16 expression was significantly increased in subcutaneous fat, peripheral blood mononuclear cells, and serum after 6 months of testosterone therapy.

• PRDM16 expression was significantly increased in SCF after 6 months of T therapy compared to baseline.
• PRDM16 expression was significantly increased in PBMC after 6 months of T therapy compared to baseline.
• Circulating serum PRDM16 protein levels measured by ELISA were significantly increased after 6 months of T therapy.
• The increase in PRDM16 is described as an 'adipo-myogenic switch' and is proposed to be driven by increased estradiol levels resulting from T therapy.
• PRDM16 upregulation was observed across multiple tissue compartments, suggesting a systemic effect.

The study proposes that increased estradiol resulting from testosterone therapy is the likely driver of enhanced PRDM16 activity.

• The concurrent increase in estradiol and PRDM16 after T therapy supports estradiol as a mediator of PRDM16 upregulation.
• PRDM16 is characterized in this study as an 'adipo-myogenic switch' that mediates the molecular shift from adipogenic to myogenic pathways.
• The authors propose that PRDM16 activity could directly or indirectly mediate the shift from the adipogenic to the myogenic pathway.
• This mechanism is proposed to explain the reduction in body fat and increase in lean mass commonly observed in hypogonadal men treated with testosterone.