Insulin and leptin oscillations license food-entrained browning and metabolic flexibility
Pamela Mattar,
Andressa Reginato,
Christian Lavados,
Debajyoti Das,
Manu Kalyani,
Nuria Martinez-Lopez,
Mridul Sharma,
Grethe Skovbjerg,
Jacob Lercke Skytte,
Urmas Roostalu,
Rajasekaran Subbarayan,
Elodie Picarda,
Xingxing Zang,
Jinghang Zhang,
Chandan Guha,
Gary Schwartz,
Prashant Rajbhandari,
Rajat Singh
Affiliations
Pamela Mattar
Department of Medicine, Division of Digestive Diseases, University of Los Angeles, Los Angeles, CA, USA
Andressa Reginato
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA
Christian Lavados
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA
Debajyoti Das
Department of Medicine, Division of Digestive Diseases, University of Los Angeles, Los Angeles, CA, USA
Manu Kalyani
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA
Nuria Martinez-Lopez
Department of Medicine, Division of Digestive Diseases, University of Los Angeles, Los Angeles, CA, USA; Comprehensive Liver Research Center at UCLA, University of Los Angeles, Los Angeles, CA, USA
Mridul Sharma
Department of Medicine, Division of Digestive Diseases, University of Los Angeles, Los Angeles, CA, USA
Grethe Skovbjerg
Gubra ApS, Hørsholm, Denmark
Jacob Lercke Skytte
Gubra ApS, Hørsholm, Denmark
Urmas Roostalu
Gubra ApS, Hørsholm, Denmark
Rajasekaran Subbarayan
Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY, USA
Elodie Picarda
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
Xingxing Zang
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
Jinghang Zhang
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
Chandan Guha
Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY, USA
Gary Schwartz
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
Prashant Rajbhandari
Department of Medicine, Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Rajat Singh
Department of Medicine, Division of Digestive Diseases, University of Los Angeles, Los Angeles, CA, USA; Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Comprehensive Liver Research Center at UCLA, University of Los Angeles, Los Angeles, CA, USA; Corresponding author
Summary: Timed feeding drives adipose browning, although the integrative mechanisms for the same remain unclear. Here, we show that twice-a-night (TAN) feeding generates biphasic oscillations of circulating insulin and leptin, representing their entrainment by timed feeding. Insulin and leptin surges lead to marked cellular, functional, and metabolic remodeling of subcutaneous white adipose tissue (sWAT), resulting in increased energy expenditure. Single-cell RNA-sequencing (scRNA-seq) analyses and flow cytometry demonstrate a role for insulin and leptin surges in innate lymphoid type 2 (ILC2) cell recruitment and sWAT browning, since sWAT depot denervation or loss of leptin or insulin receptor signaling or ILC2 recruitment each dampens TAN feeding-induced sWAT remodeling and energy expenditure. Consistently, recreating insulin and leptin oscillations via once-a-day timed co-injections is sufficient to favorably remodel innervated sWAT. Innervation is necessary for sWAT remodeling, since denervation of sWAT, but not brown adipose tissue (BAT), blocks TAN-induced sWAT remodeling and resolution of inflammation. In sum, reorganization of nutrient-sensitive pathways remodels sWAT and drives the metabolic benefits of timed feeding.
