miR-375 is cold exposure sensitive and drives thermogenesis in visceral adipose tissue derived stem cells.

Activation of brown adipose tissue may increase energy expenditure by non-shivering thermogenesis. Cold exposure is one of the options to activate brown adipocytes. To link changes in energy metabolism with microRNA expression (miRNAs), we analyzed 158 miRNAs in serum of 169 healthy individuals before and after cold exposure. Validating the results of a miRNA array, a significant down-regulation of miR-375 after cold exposure (P < 0.0001) was detected. These changes went along with a significant negative correlation between miR-375 and visceral adipose tissue (VAT) mass (P < 0.0001), implicating a specific function of miR-375 in this depot. Significantly higher expression levels of miR-375 were found in VAT in comparison to subcutaneous fat (SAT). Using in silico prediction, we identified putative miR-375 target genes involved in the thermogenesis pathway. Cold-stimulation of subcutaneous and visceral pre-adipocytes (PACs) led to significantly higher expression levels of FABP4, FGF21, PPARGC1A and PRDM16 in VC-PACs. Analyzing miR-375 knock down and cold stimulated VC-PACs revealed a significant up-regulation of thermogenesis associated genes PPARGC1A, ELOVL3 and PRDM16. In summary, our findings identified miR-375 as a potential adipogenic and thermogenesis-associated miRNA exclusively acting in visceral adipose tissue.

Effect of BMI on the Thermogenic Response to Cold Exposure and Associated Changes in Metabolism and Browning Markers in Adult Humans.

INTRODUCTION: Brown adipose tissue (BAT) serves to produce heat by nonshivering thermogenesis. Activation of BAT increases energy expenditure and is seen as a putative strategy to treat obesity. There are conflicting data on the capacity for cold-induced thermogenesis in individuals with higher BMI. METHODS: To investigate the effect of BMI on cold-induced stimulation of energy expenditure, changes in the metabolic profile, and the expression of browning markers in subcutaneous white adipose tissue (scWAT), healthy adults (N = 173, 50.9% females) with a median age of 26.0 (interquartile range [IQR]: 23.0; 28.0) years and a median body mass index (BMI) of 23.6 [IQR: 21.9; 26.6] kg/m2 were exposed to short-term mild cold exposure (CE). Resting energy expenditure (REE) was measured by indirect calorimetry and blood sampling was conducted at baseline and after CE. In a subgroup of participants with obesity, subcutaneous abdominal fat biopsies were taken before and after CE. RESULTS: The cold-induced median increase in REE was 74 (IQR: -28; 241) kcal/day (p < 0.001). This increase negatively correlated with BMI (p < 0.001). Participants with BMI 18.5-24.9 kg/m2 displayed a significant median increase of 103 kcal/day (p < 0.001), participants with overweight or obesity were not able to increase REE (23, p = 0.468 or -30 kcal/day, p = 0.917, respectively). In participants with obesity, expression of cell death activator in scWAT after CE was upregulated in females (p = 0.034). CONCLUSIONS: Persons with overweight and obesity do not increase REE in response to CE, presumably reflecting lower BAT activity. Likewise, the metabolic response to cold is diminished in participants with elevated BMI.