EFFECTS OF AGING AND A HIGH-FAT DIET ON BODY-WEIGHT AND GLUCOSE-TOLERANCE IN GLUCAGON-LIKE PEPTIDE-1 RECEPTOR(- -) MICE/

Disruption of glucagon-like peptide-1 (GLP-1) receptor signaling in mi ce results in mild glucose intolerance, principally due to elimination of the incretin effect of GLP-1. Despite the inhibitory effects of GL P-1 on food intake, 6- to 8-week-old GLP-1 receptor(-/-) (GLP-1R(-/-)) mice were not obese and did not exhibit disturbances of feeding behav ior. As both diabetes and obesity frequently become more phenotypicall y evident in older rodents, we studied the consequences of aging and a high fat diet on glucose control and body weight in GLP-1R(-/-) mice. No evidence of obesity or deterioration in glucose control was detect ed in 11- and 16-month-old GLP-1R(-/-) mice (mean weight, 34.7 +/- 2.0 , 30.5 +/- 1.5, and 34.6 +/- 2.8 g in male and 25.3 +/- 1.6, 28.4 +/- 1.2, and 31.9 +/- 2.9 gin female GLP-1R(+/+), GLP-1R(+/-), and GLP-1R( -/-) mice, respectively; P = NS). After 18 weeks of high fat feeding, GLP-1R(-/-) mice gained similar (males) or less (females) weight than age- and sex-matched CD1 controls. No significant deterioration in glu cose tolerance was observed after high fat feeding in GLP-1R(-/-) mice . These observations demonstrate that long term disruption of GLP-1 si gnaling in the central nervous system and peripheral tissues of older mice is not associated with the development of obesity or deterioratio n in glucose homeostasis.