PMID- 29410348 OWN - NLM STAT- MEDLINE DCOM- 20190128 LR - 20231103 IS - 1532-8600 (Electronic) IS - 0026-0495 (Print) IS - 0026-0495 (Linking) VI - 83 DP - 2018 Jun TI - Caloric restriction improves glucose homeostasis, yet increases cardiometabolic risk in caveolin-1-deficient mice. PG - 92-101 LID - S0026-0495(18)30018-0 [pii] LID - 10.1016/j.metabol.2018.01.012 [doi] AB - BACKGROUND AND PURPOSE: The plasma membrane protein caveolin-1 (CAV-1) has been shown to be involved in modulating glucose homeostasis and the actions of the renin-angiotensin-aldosterone system (RAAS). Caloric restriction (CR) is widely accepted as an effective therapeutic approach to improve insulin sensitivity and reduce the severity of diabetes. Recent data indicate that polymorphisms of the CAV-1 gene are strongly associated with insulin resistance, hypertension and metabolic abnormalities in non-obese individuals. Therefore, we sought to determine whether CR improves the metabolic and cardiovascular (CV) risk factors in the lean CAV-1 KO mice. MATERIALS/METHODS: Twelve- to fourteen-week-old CAV-1 knockout (KO) and genetically matched wild-type (WT) male mice were randomized by genotype to one of two dietary regimens: ad libitum (ad lib) food intake or 40% CR for 4 weeks. Three weeks following the onset of dietary restriction, all groups were assessed for insulin sensitivity. At the end of the study, all groups were assessed for fasting glucose, insulin, HOMA-IR, lipids, corticosterone levels and blood pressure (BP). Aldosterone secretion was determined from acutely isolated Zona Glomerulosa cells. RESULTS: We confirmed that the CAV-1 KO mice on the ad lib diet display a phenotype consistent with the cardiometabolic syndrome, as shown by higher systolic BP (SBP), plasma glucose, HOMA-IR and aldosterone levels despite lower body weight compared with WT mice on the ad lib diet. CAV-1 KO mice maintained their body weight on the ad lib diet, but had substantially greater weight loss with CR, as compared to caloric restricted WT mice. CR-mediated changes in weight were associated with dramatic improvements in glucose and insulin tolerance in both genotypes. These responses to CR, however, were more robust in CAV-1KO vs. WT mice and were accompanied by reductions in plasma glucose, insulin and HOMA-IR in CAV-1KO but not WT mice. Surprisingly, in the CAV-1 KO, but not in WT mice, CR was associated with increased SBP and aldosterone levels, suggesting that in CAV-1 KO mice CR induced an increase in some CV risk factors. CONCLUSIONS: CR improved the metabolic phenotype in CAV-1 KO mice by increasing insulin sensitivity; nevertheless, this intervention also increased CV risk by inappropriate adaptive responses in the RAAS and BP. CI - Copyright (c) 2018. Published by Elsevier Inc. FAU - Mayurasakorn, Korapat AU - Mayurasakorn K AD - Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Hasanah, Nurul AU - Hasanah N AD - Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Universiti Teknologi MARA, Kuala Lumpur, Malaysia. FAU - Homma, Tsuyoshi AU - Homma T AD - Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Homma, Mika AU - Homma M AD - Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Rangel, Isis Katayama AU - Rangel IK AD - Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Garza, Amanda E AU - Garza AE AD - Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Romero, Jose R AU - Romero JR AD - Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Adler, Gail K AU - Adler GK AD - Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Williams, Gordon H AU - Williams GH AD - Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Pojoga, Luminita H AU - Pojoga LH AD - Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: lpojoga@partners.org. LA - eng GR - K24 HL103845/HL/NHLBI NIH HHS/United States GR - R01 HL087060/HL/NHLBI NIH HHS/United States GR - T32 HL007609/HL/NHLBI NIH HHS/United States GR - R01 HL069208/HL/NHLBI NIH HHS/United States GR - R01 HL104032/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180202 PL - United States TA - Metabolism JT - Metabolism: clinical and experimental JID - 0375267 RN - 0 (Blood Glucose) RN - 0 (Caveolin 1) SB - IM MH - Animals MH - Blood Glucose/*metabolism MH - Blood Pressure/physiology MH - *Caloric Restriction/adverse effects MH - Cardiovascular Diseases/*genetics/*metabolism MH - Caveolin 1/*genetics MH - Homeostasis/genetics MH - Insulin Resistance/genetics MH - Male MH - Metabolic Syndrome/*genetics/*metabolism MH - Mice MH - Mice, Knockout MH - Renin-Angiotensin System/physiology MH - Risk Factors PMC - PMC10619427 MID - NIHMS946218 OTO - NOTNLM OT - Aldosterone OT - Caloric restriction OT - Cardiometabolic dysfunction OT - Caveolin OT - Insulin resistance OT - The metabolic syndrome COIS- DISCLOSURES There is no conflict of interest. EDAT- 2018/02/08 06:00 MHDA- 2019/01/29 06:00 PMCR- 2023/11/01 CRDT- 2018/02/08 06:00 PHST- 2017/09/27 00:00 [received] PHST- 2017/12/18 00:00 [revised] PHST- 2018/01/17 00:00 [accepted] PHST- 2018/02/08 06:00 [pubmed] PHST- 2019/01/29 06:00 [medline] PHST- 2018/02/08 06:00 [entrez] PHST- 2023/11/01 00:00 [pmc-release] AID - S0026-0495(18)30018-0 [pii] AID - 10.1016/j.metabol.2018.01.012 [doi] PST - ppublish SO - Metabolism. 2018 Jun;83:92-101. doi: 10.1016/j.metabol.2018.01.012. Epub 2018 Feb 2.