Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe earlyonset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10-16 , n=3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity. * Call rate to exclude individuals for whom genotyping success rate is less than a certain percentage (to exclude 'bad' samples/DNA) **Exome-chip samples from this study CHOP: The authors thank the network of primary care clinicians and the patients and families for their contribution to this project and to clinical research facilitated by the Pediatric Research Consortium [PeRC]-The Children's Hospital of Philadelphia. R. Chiavacci, E. Dabaghyan, A.

Introductory The maintenance of proteostasis is crucial for any organism to survive and reproduce in an ever-changing environment, but its efficiency declines with age1. Posttranscriptional regulators such as microRNAs control protein translation of target mRNAs with major consequences for development, physiology, and longevity2,3. Here we show that food odor stimulates organismal proteostasis and promotes longevity in Caenorhabditis elegans through mir-71-mediated inhibition of tir-1 mRNA stability in olfactory AWC neurons. Screening a collection of microRNAs that control aging3 we find that miRNA mir-71 regulates lifespan and promotes ubiquitin-dependent protein turnover, particularly in the intestine. We show that mir-71 directly inhibits the toll receptor domain protein TIR-1 in AWC olfactory neurons and that disruption of mir-71/tir-1 or loss of AWC olfactory neurons eliminates the influence of food source on proteostasis. mir-71-mediated regulation of TIR-1 controls chemotactic behavior and is regulated by odor. Thus, odor perception influences cell-type specific miRNA-target interaction to regulate organismal proteostasis and longevity. We anticipate that the proposed mechanism of food perception will stimulate further research on neuroendocrine brain-to-gut communication and may open the possibility for therapeutic interventions to improve proteostasis and organismal health via the sense of smell, with potential implication for obesity, diabetes and aging.

Polymorphonuclear cells (PMNs) attend to inflammatory sites by chemotactic movement, caused by chemoattractants (CAs) like n-formyl-l-methionyl-l-leucyl-l-phenylalanine (FMLP) and interleukin-8 (IL-8). However, distinct but applicable assays for investigations of PMNs' migration limit in vitro examination. We integrated CD15-bead-based isolation of PMNs with analysing their chemotaxis in a novel 3D-µ-Slide migration chamber. The PMNs were exposed to different concentrations of FMLP and IL-8 (1, 10 and 100 nM) and observed for 180 min in cell-physiological environment conditions. Moving PMNs' percentage (median and interquartile range) decreased from 62% (27%) to 36% (31%) without CA, from 88% (30%) to 22% (26%) for 1 nM IL-8, from 70% (22%) to 28% (13%) for 100 nM IL-8, from 30% (23%) to 18% (46%) for 1 nM FMLP and from 76% (20%) to 28% (13%) for 100 nM FMLP. Centres of cell movement turned towards the CAs (negative values) within a single 30-min observation period: 5.37 µm (16.82 µm) without CA, −181.37 µm (132.18 µm) with 10 nM and −239.34 µm (152.19 µm) with 100 nM IL-8; −116.2 µm (69.07 µm) with 10 nM and −71.59 µm (98.58 µm) with 100 nM FMLP. FMLP and IL-8 ensure chemotaxis without increase of chemokinesis. 3D-µ-Slide chemotaxis chambers facilitate time course analyses of PMNs' migration in stable conditions over a long time with concise distinction of chemotaxis and chemokinesis.