Mice lacking hepatic lipase are lean and protected against diet-induced obesity and hepatic steatosis.
Hepatic lipase (HL)-mediated lipoprotein hydrolysis provides free fatty acids for energy, storage, and nutrient signaling and may play a role in energy homeostasis. Because HL-activity increases with increased visceral fat, we hypothesized that increased HL-activity favors weight gain and obesity and consequently, that HL deficiency would reduce body fat stores and protect against diet-induced obesity. To test this hypothesis, we compared wild-type mice (with endogenous HL) and mice genetically deficient in HL with respect to daily body weight and food intake, body composition, and adipocyte size on both chow and high-fat (HF) diets. Key determinants of energy expenditure, including rate of oxygen consumption, heat production, and locomotor activity, were measured by indirect calorimetry. HL-deficient mice exhibited reduced weight gain on both diets (by 32%, chow; by 50%, HF; both P < 0.0001, n = 6-7 per genotype), effects that were associated with reduced average daily food intake (by 22-30% on both diets, P < 0.0001) and a modest increase in the rate of oxygen consumption (by 25%, P < 0.003) during the light cycle. Moreover, in mice fed the HF diet, HL deficiency reduced both body fat (by 30%, P < 0.0001) and adipocyte size (by 53%, P < 0.01) and fully prevented the development of hepatic steatosis. Also, HL deficiency reduced adipose tissue macrophage content, consistent with reduced inflammation and a lean phenotype. Our results demonstrate that in mice, HL deficiency protects against diet-induced obesity and its hepatic sequelae. Inhibition of HL-activity may therefore have value in the prevention and/or treatment of obesity.
Chiu
Harvey K
HK
Department of Pediatrics, University of Washington, 1959 NE Pacific Street, Seattle, Washington 98195, USA.
Qian
Kun
K
Ogimoto
Kayoko
K
Morton
Gregory J
GJ
Wisse
Brent E
BE
Agrawal
Nalini
N
McDonald
Thomas O
TO
Schwartz
Michael W
MW
Dichek
Helén L
HL
D000273:Adipose Tissue / Q000166:cytology / Q000276:immunology; D050154:Adiposity; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002940:Circadian Rhythm; D004041:Dietary Fats / Q000009:adverse effects; D004435:Eating; D004734:Energy Metabolism; D005234:Fatty Liver / Q000201:enzymology* / Q000209:etiology; D005260:Female; D005951:Glucose Tolerance Test; D008049:Lipase / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008124:Locomotion; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000201:enzymology* / Q000209:etiology; D010101:Oxygen Consumption; D022722:Thermogenesis; D014280:Triglycerides / Q000378:metabolism
D001786:Blood Glucose; D004041:Dietary Fats; D014280:Triglycerides; D008049:Lipase; C495700:Lipc protein, mouse