Reduced glycoprotein hormone β5 links male aging and testosterone decline to increased adiposity.

Blood levels of GPHB5 were negatively correlated with men's ages and positively correlated with circulating testosterone in clinical samples.

• The correlation between GPHB5 and age was negative, suggesting GPHB5 declines as men age.
• The positive correlation between GPHB5 and circulating testosterone indicates GPHB5 tracks testosterone levels.
• This relationship was observed in clinical (human) samples.
• No such age- or testosterone-dependent relationship was described for women in this context.

Testosterone directly stimulated the expression of GPHB5 in cultured cells via androgen receptor (AR) signaling.

• Pharmacological blockade of androgen receptor (AR) functions abrogated the testosterone-induced upregulation of GPHB5 expression.
• This establishes a direct transcriptional or regulatory link between AR activation and GPHB5 production.
• The effect was demonstrated in cell culture experiments.

Knockout of androgen receptor (AR) in mice led to both development of obesity and reduction of GPHB5 expression.

• AR knockout animals developed obesity, consistent with the known catabolic role of androgen signaling in adipose tissue.
• GPHB5 expression was reduced in AR knockout mice, supporting GPHB5 as downstream of AR signaling.
• These findings link AR-mediated regulation of GPHB5 to body adiposity.

Genetic ablation of GPHB5 caused severe obesity specifically in male mice but not in female mice.

• GPHB5 knockout in males reduced the browning of white adipose tissue.
• GPHB5 knockout in males diminished energy expenditure.
• Female GPHB5 knockout mice did not develop the same obese phenotype, indicating a sex-specific role.
• This sex-specific effect aligns with the proposed intermediary role of GPHB5 in male testosterone-driven adiposity regulation.

Elevated blood testosterone levels did not exert catabolic actions in GPHB5-/- mice, demonstrating GPHB5 is required for testosterone's fat-reducing effects.

• In the absence of GPHB5, testosterone's known catabolic effect on adipose tissue was abolished.
• This result provides evidence that testosterone acts on adipose tissue through GPHB5 rather than through direct action on adipocytes.
• The finding addresses previously accumulated evidence that did not support direct testosterone action in adipocyte lipid metabolism.

Recombinant GPHB5 protein administration stimulated energy expenditure and reduced adiposity.

• Exogenous recombinant GPHB5 protein was sufficient to stimulate energy expenditure.
• Recombinant GPHB5 protein reduced adiposity in treated animals.
• These pharmacological results support GPHB5 as a functional intermediary hormone with therapeutic potential.

The paper proposes that unlike estrogen's direct action on adipocytes in women, testosterone's catabolic effect on adipose tissue in men is mediated indirectly through GPHB5.

• Aging causes decline of testosterone in men and estrogen in women, both leading to fat accumulation.
• Estrogen's direct action on adipocytes explains fat regulation in women.
• Accumulative evidence does not support direct testosterone action in adipocyte lipid metabolism, necessitating an intermediary.
• GPHB5 is proposed as this missing intermediary link between testosterone signaling and adipose tissue catabolism.