Adipocyte hypertrophy is associated with lysosomal permeability both in vivo and in vitro: role in adipose tissue inflammation.
Obesity in both humans and rodents is characterized by adipocyte hypertrophy and the presence of death adipocytes surrounded by macrophages forming "crown-like structures." However, the biochemical pathways involved in triggering adipocyte death as well as the role of death adipocytes in adipose tissue remodeling and macrophage infiltration remain poorly understood. We now show that induction of adipocyte hypertrophy by incubation of mature adipocytes with saturated fatty acids results in lysosomal destabilization and cathepsin B (ctsb), a key lysosomal cysteine protease, activation and redistribution into the cytosol. ctsb activation was required for the lysosomal permeabilization, and its inhibition protected cells against mitochondrial dysfunction. With the use of a dietary murine model of obesity, ctsb activation was detected in adipose tissue of these mice. This is an early event during weight gain that correlates with the presence of death adipocytes, and precedes macrophage infiltration of adipose tissue. Moreover, ctsb-deficient mice showed decreased lysosomal permeabilization in adipocytes and were protected against adipocyte cell death and macrophage infiltration to adipose tissue independent of body weight. These data strongly suggest that ctsb activation and lysosomal permeabilization in adipocytes are key initial events that contribute to the adipocyte cell death and macrophage infiltration into adipose tissue associated with obesity. Inhibition of ctsb activation may be a new therapeutic strategy for the treatment of obesity-associated metabolic complications.
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Agnieszka
A
Gornicka
Jade
J
Fettig
Akiko
A
Eguchi
Michael P
MP
Berk
Samjhana
S
Thapaliya
Laura J
LJ
Dixon
Ariel E
AE
Feldstein
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D059305:Diet, High-Fat / Q000009:adverse effects; D004789:Enzyme Activation / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000009:adverse effects; D006984:Hypertrophy; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058990:Molecular Targeted Therapy; D009765:Obesity / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010539:Permeability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects
D015853:Cysteine Proteinase Inhibitors; D005230:Fatty Acids, Nonesterified; D002401:Cathepsin B; C533915:Ctsb protein, mouse