Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 117, Issue 11, Pages 3271-3282Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI31929
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Funding
- NHLBI NIH HHS [P01 HL020948, HL20948, HL63762, R01 HL063762, R37 HL063762] Funding Source: Medline
- NIDDK NIH HHS [DK056863, R01 DK074932, T35 DK060444, P01 DK056863, DK069987, DK74932, R01 DK069987] Funding Source: Medline
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Diet-induced obesity and its serious consequences such as diabetes, cardiovascular disease, and cancer are rapidly becoming a major global health threat. Therefore, understanding the cellular and molecular mechanisms by which dietary fat causes obesity and diabetes is of paramount importance in order to identify preventive and therapeutic strategies. Increased dietary fat intake results in high plasma levels of triglyceride-rich lipoproteins (TGRL). Tissue uptake of TGRL has been shown to promote glucose intolerance. We generated mice with an adipocyte-specific inactivation of the multifunctional receptor LDL receptor-related protein-1 (LRP1) to determine its role in mediating the effects of TGRL on diet-induced obesity and diabetes. Knockout mice displayed delayed postprandial lipid clearance, reduced body weight, smaller fat stores, lipid-depleted brown adipocytes, improved glucose tolerance, and elevated energy expenditure due to enhanced muscle thermogenesis. We further demonstrated that inactivation of adipocyte LRP1 resulted in resistance to dietary fat-induced obesity and glucose intolerance. These findings identify LRP1 as a critical regulator of adipocyte energy homeostasis, where functional disruption leads to reduced lipid transport, increased insulin sensitivity, and muscular energy expenditure.
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