Food-seeking behavior is triggered by skin ultraviolet exposure in males

Sexual dimorphisms are responsible for profound metabolic differences in health and behavior. Whether males and females react differently to environmental cues, such as solar ultraviolet (UV) exposure, is unknown. Here we show that solar exposure induces food-seeking behavior, food intake, and food-seeking behavior and food intake in men, but not in women, through epidemiological evidence of approximately 3,000 individuals throughout the year. In mice, UVB exposure leads to increased food-seeking behavior, food intake and weight gain, with a sexual dimorphism towards males. In both mice and human males, increased appetite is correlated with elevated levels of circulating ghrelin. Specifically, UVB irradiation leads to p53 transcriptional activation of ghrelin in skin adipocytes, while a conditional p53-knockout in mice abolishes UVB-induced ghrelin expression and food-seeking behavior. In females, estrogen interferes with the p53–chromatin interaction on the ghrelin promoter, thus blocking ghrelin and food-seeking behavior in response to UVB exposure. These results identify the skin as a major mediator of energy homeostasis and may lead to therapeutic opportunities for sex-based treatments of endocrine-related diseases.


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March 2021
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Sample size was chosen as acceptable in the field of behavioural experiments, upon consulting with leading experts: Dr. Shamgar, Dr. Weller and Dr. Bikovski. Detailed description of the statistical methods used for the analyse, appears in the paper.
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The authentication of the pre-adipocytes (HWP, 3T3-L1 and LiSa-2) was done using the Oil Red O Staining for the validation of the lipid droplets. Other cell lines mentioned in the study were not authenticated by us.

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All mice used were from C57BL/6 background. All mice were housed in individually ventilated cages (IVC) (Maximum 5 mice per cage) for 12 hours dark/12 hours light phases with 22+1o C temperature and 32-35% humidity. Wild-type C57BL/6 mice (males and females) aged 6-8 weeks were purchased from Envigo. p53-knockout in mice p53flx/flx mice were a gift from Eli Pikarksky (The Hebrew University of Jerusalem, Israel), and mice with the Fabp4 promoter directing expression of Cre recombinase (Fabp4Cre+) were purchased from Jackson Laboratory. These FABP4Cre+ transgenic mice were used as a Cre-lox tool for deletion of p53 floxed sequences in white adipose tissue. The p53 knockout in white adipose tissue was validated by genotyping.

March 2021
OVX mice We performed the OVX and sham surgeries under the supervision of the Tel Aviv University Veterinarians and the OVX surgery was validated for the reduction of the circulating estrogen levels as mentioned in the manuscript.

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All animal experiments were performed in accordance with guidelines of the Tel Aviv University Institutional Animal Care and Use Committee with institutional policies and approved protocols.
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Population characteristics
For Human cohort study The human cohort study was approved by Tel Aviv University Ethics Committee under ethics number #0000668-2. Subjects were (aged 18-55 years) were recruited (self-volunteer) convenience sampling and were given the consent form with all the relevant information about the experiment. To avoid skin tone bias, all the participants in our study had Fitzpatrick Skin Type II-III. Since our study is to compare the solar UVB effects on males and females we took into consideration both genders. Subjects that were not included in the study were the pregnant women and metabolic diseases related -e.g. diabetes. No genotyping information was collected or tested during the experiment. The subjects on the past or current medications were noted by the medical doctor Dr. Tom Ben-Dov who performed the blood draws.
For UVB phototherapy questionnaire UVB phototherapy questionnaire was conducted in the Tel Aviv Sourasky Medical Center and Assuta Hospital in Israel under approved Helsinki 0151-17-TLV and 17-ASMC-17. All the participants were recruited by convenience sampling and asked to sign an informed consent form. The sample consisted 43.7% males and 56.3% females. Data were collected through selfreported questionnaires (translated in Hebrew) before exposure to the UVB dose (T1) and10-12 exposure sessions for a month and after the treatment (T2). Genotyping-related information of the phototherapy subjects was neither collected nor tested in this study.

Recruitment
For Human cohort study The human cohort study was approved by Tel Aviv University Ethics Committee under ethics number #0000668-2. Subjects were (aged 18-55 years) were recruited (self-volunteer) convenience sampling and were given the consent form with all the relevant information about the experiment. To avoid skin tone bias, all the participants in our study had Fitzpatrick Skin Type II-III.
For UVB phototherapy questionnaire UVB phototherapy questionnaire was conducted in the Tel Aviv Sourasky Medical Center and Assuta Hospital in Israel under approved Helsinki 0151-17-TLV and 17-ASMC-17.Patients undergoing UVB phototherapy included phototherapy-responsive dermatoses including psoriasis, atopic dermatitis, mycosis fungoides, and general pruritus (aged 20-82). Skin tone directly affects the amount of UVB that penetrates the skin, and probably influences the response. To avoid this bias, most of the patients in our study had Fitzpatrick Skin Type II-III, and their treatment protocol was determined by the physician accordingly (i.e., higher skin tone will receive higher dose).

Ethics oversight
The human cohort study was approved by Tel Aviv University Ethics Committee under ethics number #0000668-2. The UVB phototherapy questionnaire was conducted in the Tel Aviv Sourasky Medical Center and Assuta Hospital in Israel under approved Helsinki 0151-17-TLV and 17-ASMC-17. The human skin explants from the patients undergoing abdominoplasty surgery at the Wolfson Medical Center, Israel were obtained under approved Helsinki number: 0015-16-WOMC.
All animal experiments were performed in accordance with the guidelines of the Tel Aviv University Institutional Animal Care and Use Committee with institutional policies and approved protocols (IACUC permit: 01-15-086 and 01-19-003).
Note that full information on the approval of the study protocol must also be provided in the manuscript.