Conventional dendritic cells (cDCs) scan and integrate environmental cues in almost every tissue, including exogenous metabolic signals. While cDCs are critical in maintaining immune balance, their role in preserving energy homeostasis is unclear. Here, we showed that Batf3-deficient mice lacking conventional type 1 DCs (cDC1s) had increased body weight and adiposity during aging. This led to impaired energy expenditure and glucose tolerance, insulin resistance, dyslipidemia, and liver steatosis. cDC1 deficiency caused adipose tissue inflammation that was preceded by a paucity of NK1.1+ invariant NKT (iNKT) cells. Accordingly, among antigen-presenting cells, cDC1s exhibited notable induction of IFN-γ production by iNKT cells, which plays a metabolically protective role in lean adipose tissue. Flt3L treatment, which expands the dendritic cell (DC) compartment, mitigated diet-induced obesity and hyperlipidemia in a Batf3-dependent manner. This effect was partially mediated by NK1.1+ cells. These results reveal a new critical role for the cDC1-iNKT cell axis in the regulation of adipose tissue homeostasis.We are grateful to the Immunology, Ophthalmology, and ENT Department at the UCM for
providing useful discussion and to Gillian Dunphy and Antonia Tomás for critically reading the manuscript. We thank the CNIC and UCM facilities. Funding: Work in the S.I. laboratory
is funded by the Spanish Ministerio de Ciencia, Innovación (MICINN), Agencia Estatal de
Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER), RTI2018-094484-BI00, and RYC-2016-19463. EHG is the recipient of an FPI fellowship (PRE2019-087509) from
the Spanish Ministry of Science and Innovation. Work in the DS laboratory is funded by
the CNIC; the European Research Council (ERC-2016-Consolidator Grant 725091); the
MICINN, AEI and FEDER (PID2019-108157RB); Comunidad de Madrid (B2017/BMD-3733
Immunothercan-CM); Atresmedia (Constantes y Vitales prize); and Fundació La Marató de
TV3 (201723). Work in the G.S. laboratory receives funding from the European Union’s
Seventh Framework Programme (FP7/2007-2013) under grant agreement n° ERC 260464,
EFSD/Lilly European Diabetes Research Programme GS, 2017 Leonardo Grant for
Researchers and Cultural Creators, BBVA Foundation (Investigadores-BBVA-2017)
IN[17]_BBM_BAS_0066, MINECO-FEDER SAF2016-79126-R, EUIN2017-85875, Comunidad
de Madrid IMMUNOTHERCAN-CM S2010/BMD-2326 and B2017/BMD-3733 and Fundación
AECC. IN receives funding from EFSD/Lilly (2019), EFSD Rising star (2019), and JdC—
Incorporation (IJC2018-035390-I). The CNIC is supported by the Instituto de Salud Carlos III
(ISCIII), the MICINN, and the Pro CNIC Foundation.S
