Another major regulator of mTORC1 is Forkhead box protein O1 (FOXO1), which is a transcription factor that regulates mTORC1 through sestrin 3.31,32 Sestrin 3 is a stress-induced protein that helps regulate blood glucose and promote insulin sensitivity.33 When FOXO1 is translocated to the cell nucleus, it upregulates the expression of sestrin 3, resulting in mTORC1 inhibition.31,32 Insulin, IGF-1, and nutrient excess lead to FOXO1 translocation to the cell cytoplasm where it can no longer mitigate mTORC1 activity, while the fasted state leads to translocation to the nucleus.34 A single study evaluated the association between FOXO1, mTORC1, a high glycemic–load diet, and acne development. Immunohistochemical detection of mTORC1 assessed by digital image analysis revealed significantly greater expression in inflamed pilosebaceous units found in acne patients (P<.001). Immunohistochemical cytoplasmic expression of FOXO1 and mTOR (used as a proxy for mTORC1) was significantly higher in patients on a high glycemic–load diet (P=.021 and P=.009, respectively) as well as in patients with more severe forms of acne (P=.005 and P=.015, respectively) and elevated IGF-1 levels (P=.004 and P=.003, respectively).21
mTORC1 contributes to the proliferation of keratinocytes and excess sebum production, both independently and through androgen-mediated processes.35-40 Insulinlike growth factor 1 binding the IGF-1 receptor leads to proliferation of keratinocytes lining the sebaceous gland and hair follicle in vivo.35 In mice with epidermis-specific deletion of mTOR, keratinocyte proliferation was decreased and hair follicles were diminished both in number and development. Genetic loss of mTOR in the epidermis led to attenuated signaling pathways of mTORC1 and mTORC2.36
Androgen function is augmented by mTORC1, FOXO1, and IGF-1 through several mechanisms, which may partially explain the hormonal relationship to acne. Androgens increase IGF-1 within the hair follicle.37 In prostate cancer cells, IGF-1 then facilitates movement of FOXO1 to the cytoplasm, preventing it from blocking mTORC1. This effective inactivation of FOXO1 thus further augments the impact of androgens by both allowing unchecked mTORC1 pathway activity and increasing translocation of the androgen receptor (AR) to the nucleus where it exerts its effects.38 Interestingly, genetic polymorphisms of the AR have been shown to cause variable affinity of FOXO1 for the AR; specifically, shorter CAG (cytosine, adenine, guanine) repeat length may lead to decreased FOXO1 binding and is associated with an increased risk for acne.41-43 In addition to its effects on the hair follicle, IGF-1 stimulates production of testosterone and dehydroepiandrosterone as well as activates 5α-reductase, leading to higher dihydrotestosterone levels, which activate the AR with higher affinity than testosterone.44 In some tissues, androgens help regulate the mTORC1 pathway through positive feedback loops.45,46 At this time, we do not know if this occurs in the pathogenesis of acne.
Isotretinoin is the treatment of choice for refractory acne. It has been hypothesized that isotretinoin induces sebocyte apoptosis via the upregulation of FOXO transcription factors and p53.47 Elevated levels of nuclear FOXO1 have been found in the sebaceous glands of patients following initiation of treatment with isotretinoin and are hypothesized to play a major role in the drug’s effectiveness. Specifically, biopsies from 14 acne patients before and after 6 weeks of isotretinoin therapy were analyzed with immunohistochemical staining and found to have a significantly improved nuclear to cytoplasmic ratio of nonphosphorylated FOXO1 (P<.001).47
Practical Recommendations
Given the available evidence, it is important for dermatologists to address dietary recommendations in acne patients. Although large randomized controlled trials on diet and acne severity are challenging to conduct in this population, the existing literature suggests that patients should avoid high glycemic index simple sugars and processed grains, and patients should focus on eating more complex carbohydrates in the form of legumes, vegetables, fruits, and tubers.6-8 With regard to dairy, milk (especially skim) has been associated with increased risks for acne.11,13 Fermented dairy products may have less impact on acne severity and include cheese, yogurt (unsweetened to keep glycemic index low), and sour cream.12 Additionally, dermatologists can consider evaluating acne patients for insulin resistance with a hemoglobin A1c or oral glucose tolerance test; however, these are not perfect markers of insulin sensitivity. This should be considered in patients with clinical features suggesting metabolic derangement such as acanthosis nigricans; elevated nonfasting triglycerides; or symptoms of polycystic ovarian syndrome, which include irregular menstruation, hirsutism, and early-onset androgenetic alopecia (also an independent sign of insulin resistance in men).48-51