Deletion of tumor necrosis factor-alpha receptor 1 (TNFR1) protects against diet-induced obesity by means of increased thermogenesis.
In diet-induced obesity, hypothalamic and systemic inflammatory factors trigger intracellular mechanisms that lead to resistance to the main adipostatic hormones, leptin and insulin. Tumor necrosis factor-alpha (TNF-alpha) is one of the main inflammatory factors produced during this process and its mechanistic role as an inducer of leptin and insulin resistance has been widely investigated. Most of TNF-alpha inflammatory signals are delivered by TNF receptor 1 (R1); however, the role played by this receptor in the context of obesity-associated inflammation is not completely known. Here, we show that TNFR1 knock-out (TNFR1 KO) mice are protected from diet-induced obesity due to increased thermogenesis. Under standard rodent chow or a high-fat diet, TNFR1 KO gain significantly less body mass despite increased caloric intake. Visceral adiposity and mean adipocyte diameter are reduced and blood concentrations of insulin and leptin are lower. Protection from hypothalamic leptin resistance is evidenced by increased leptin-induced suppression of food intake and preserved activation of leptin signal transduction through JAK2, STAT3, and FOXO1. Under the high-fat diet, TNFR1 KO mice present a significantly increased expression of the thermogenesis-related neurotransmitter, TRH. Further evidence of increased thermogenesis includes increased O(2) consumption in respirometry measurements, increased expressions of UCP1 and UCP3 in brown adipose tissue and skeletal muscle, respectively, and increased O(2) consumption by isolated skeletal muscle fiber mitochondria. This demonstrates that TNF-alpha signaling through TNFR1 is an important mechanism involved in obesity-associated defective thermogenesis.
Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil.
Talita
T
Romanatto
Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil.
Erika A
EA
Roman
Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil.
Ana P
AP
Arruda
Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil.
Raphael G
RG
Denis
Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil.
Carina
C
Solon
Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil.
Marciane
M
Milanski
Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil.
Juliana C
JC
Moraes
Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil.
Maria L
ML
Bonfleur
Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil.
Giovanna R
GR
Degasperi
Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil.
Paty K
PK
Picardi
Department of Physiology and Biophysics, University of São Paulo, 05508-900 São Paulo, Brazil.
Sandro
S
Hirabara
Department of Physiology and Biophysics, University of Campinas, 13084-761 São Paulo, Brazil.
Antonio C
AC
Boschero
Department of Physiology and Biophysics, University of São Paulo, 05508-900 São Paulo, Brazil.
Rui
R
Curi
Laboratory of Cell Signaling, University of Campinas, 13084-761 São Paulo, Brazil. Electronic address: lavelloso@fcm.unicamp.br.
Licio A
LA
Velloso
D050153:Abdominal Fat / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D004032:Diet / Q000009:adverse effects; D004041:Dietary Fats / Q000009:adverse effects; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption; D051381:Rats; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D022722:Thermogenesis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3
D004041:Dietary Fats; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D007473:Ion Channels; D020738:Leptin; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; C506236:Tnfrsf1a protein, mouse; C506237:Tnfrsf1a protein, rat; D014409:Tumor Necrosis Factor-alpha; C000604372:Ucp1 protein, mouse; C000604373:Ucp1 protein, rat; C000604393:Ucp3 protein, mouse; C000604394:Ucp3 protein, rat; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3; C074639:Foxo1 protein, rat; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat; D053614:Janus Kinase 2