Uthra Rajamani, Andrew R Gross, Brooke E Hjelm, Adolfo Sequeira, Marquis P Vawter, Jie Tang, Vineela Gangalapudi, Yizhou Wang, Allen M Andres, Roberta A Gottlieb, Dhruv Sareen
Author Information
Uthra Rajamani: Board of Governors, Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Andrew R Gross: Board of Governors, Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Brooke E Hjelm: Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA 92868, USA.
Adolfo Sequeira: Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA 92868, USA.
Marquis P Vawter: Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA 92868, USA.
Jie Tang: Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Vineela Gangalapudi: Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Yizhou Wang: Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Allen M Andres: Metabolism and Mitochondrial Research Core, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Roberta A Gottlieb: Metabolism and Mitochondrial Research Core, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Dhruv Sareen: Board of Governors, Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; iPSC Core, The David Janet Polak Foundation Stem Cell Core Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: dhruv.sareen@cshs.org.
The hypothalamus contains neurons that integrate hunger and satiety endocrine signals from the periphery and are implicated in the pathophysiology of obesity. The limited availability of human hypothalamic neurons hampers our understanding of obesity disease mechanisms. To address this, we generated human induced pluripotent stem cells (hiPSCs) from multiple normal body mass index (BMI; BMI ≤ 25) subjects and super-obese (OBS) donors (BMI ≥ 50) with polygenic coding variants in obesity-associated genes. We developed a method to reliably differentiate hiPSCs into hypothalamic-like neurons (iHTNs) capable of secreting orexigenic and anorexigenic neuropeptides. Transcriptomic profiling revealed that, although iHTNs maintain a fetal identity, they respond appropriately to metabolic hormones ghrelin and leptin. Notably, OBS iHTNs retained disease signatures and phenotypes of high BMI, exhibiting dysregulated respiratory function, ghrelin-leptin signaling, axonal guidance, glutamate receptors, and endoplasmic reticulum (ER) stress pathways. Thus, human iHTNs provide a powerful platform to study obesity and gene-environment interactions.
