Adiponectin knockout unexpectedly lowers blood glucose during caloric restriction, alters lipid metabolism in a sex-dependent manner in mice.

Adiponectin, the most abundant circulating hormone, typically decreases in obesity but rises during caloric restriction (CR). While adiponectin deficiency in obesity promotes cardiometabolic dysfunction, its specific roles during CR, when levels are highest, remain largely unexplored. Understanding adiponectin's function in states of leanness and energy deficit is crucial for a complete picture of its metabolic impact, especially given its complex interplay with glucose, lipid, and amino acid metabolism.

Researchers investigated the role of adiponectin by studying global adiponectin knockout (KO) in male and female mice. Mice were fed either ad libitum (AL) or a 30% CR diet from 9-13 weeks of age. The study compared KO mice to wild-type controls across both diet regimens. Key endpoints included body mass, body composition, energy expenditure, blood glucose levels (fasting and oral challenge), plasma fatty acids, systemic triglyceride clearance, and hepatic transcriptomics via RNA sequencing.

Adiponectin KO did not alter CR effects on body mass, body composition, or energy expenditure. However, KO unexpectedly decreased blood glucose levels during CR, both with fasting and following an oral glucose challenge. This effect was opposite to adiponectin deficiency during AL feeding or obesity, occurring without changes in insulin concentrations or sensitivity. Moreover, adiponectin KO augmented CR-induced increases in plasma fatty acids in both sexes. In males only, KO impaired systemic triglyceride clearance on both AL and CR diets. These lipid metabolism effects were associated with sex- and diet-specific KO effects on white adipose tissue, including altered adipocyte size and expression of key regulators of adipocyte lipid metabolism. Indirect calorimetry further revealed that adiponectin KO alters the shifts between carbohydrate and lipid utilization during fed and fasted transitions. Hepatic transcriptomics showed that, in both sexes, adiponectin KO upregulated sterol and fatty acid synthesis genes under AL, while increasing amino acid catabolic genes during CR, though without altering plasma or hepatic amino acid concentrations.

Adiponectin knockout unexpectedly decreased blood glucose levels during caloric restriction, a finding opposite to its deficiency in obesity.