Biguanides Induce Acute de novo Lipogenesis in Human Primary Sebocytes

Area of Science:

• Dermatology
• Biochemistry
• Cell Biology

Background:

• Acne pathogenesis involves increased sebum production driven by hormones and growth factors stimulating de novo lipogenesis (DNL) in sebocytes.
• Isotretinoin treats acne by inducing sebocyte apoptosis but has teratogenicity and side effects like initial acne flares.
• Metformin shows promise for acne in PCOS patients, but its efficacy in non-PCOS populations and direct effects on sebogenesis are unclear.

Purpose of the Study:

• To investigate whether biguanides directly impact sebogenesis by altering DNL in human primary sebocytes.
• To compare the effects of biguanides with isotretinoin and AICAR (an AMPK activator) on sebocyte lipogenesis and metabolism.

Main Methods:

• Measured DNL in human primary sebocytes using [14C]-acetate labeling.
• Analyzed lipid species, gene expression (qPCR), oxygen consumption, lactate production, and AMPK activation.

Main Results:

• Biguanides, isotretinoin, and azithromycin acutely increased DNL in sebocytes; AICAR inhibited it.
• Biguanides did not activate AMPK but reduced oxygen consumption and increased lactate production.
• Biguanides upregulated ACSS2 gene expression and synergized with lipogenic activators.

Conclusions:

• Biguanides acutely increase sebocyte lipogenesis, indicated by increased DNL and altered metabolic parameters.
• These findings suggest biguanides could potentially trigger an initial acne flare-up in severe acne patients.