Adipocyte caspase-8 but not RIPK3 promotes adiposity

Area of Science:

• Molecular mechanisms of cell death and inflammation
• Metabolic dysfunction in obesity
• Adipose tissue biology and pathology

Background:

• Adipocyte death drives white adipose tissue (WAT) inflammation, a key factor in obesity-related metabolic dysfunction.
• Receptor-interacting protein kinase 3 (RIPK3) mediates necroptosis, a regulated necrosis pathway implicated in inflammation.
• The specific role of adipocyte necroptosis in obesity pathogenesis is not well understood.

Purpose of the Study:

• To investigate the role of adipocyte RIPK3 in obesity and glucose homeostasis.
• To determine the involvement of RIPK3-mediated necroptosis in diet-induced obesity.
• To elucidate the interplay between caspase-8 and RIPK3 in adipocyte function.

Main Methods:

• Analysis of necroptotic signaling in WAT from diet-induced obese mice and humans.
• Generation and study of genetically modified mice with adipocyte-specific deletions of caspase-8 and RIPK3.
• In vitro studies using 3T3-L1 adipocytes with siRNA knockdown or pharmacological inhibition of caspase-8.

Main Results:

• Necroptotic signaling was elevated in WAT of obese mice and correlated with BMI in humans.
• Adipocyte-specific deletion of caspase-8 reduced adiposity in mice, an effect abolished by RIPK3 deletion.
• Deletion of the RIPK3 RHIM domain did not affect weight gain, adiposity, or glucose homeostasis in obese mice.
• Caspase-8 inhibition in adipocytes suppressed adipogenesis, potentially independently of RIPK3.

Conclusions:

• Adipocyte RIPK3's RHIM domain is not critical for obesity or glucose homeostasis.
• Caspase-8 plays a significant role in adipocyte differentiation, independent of RIPK3.
• These findings offer insights into molecular mechanisms underlying obesity and metabolic dysfunction.