Aberrantly elevated sodium/glucose cotransporter 1 (Sglt1) expression and increased glucose reabsorption contribute to obesity or lean-associated metabolic complications, however, the precise mechanisms underlying the high expression of Sglt1 and increased glucose absorption are unclear. Clock (circadian locomotor output cycles kaput protein) is known as the master clock gene; Bmal1 (basic helix-loop-helix arnt like 1) is a known heterodimer of Clock that is a critical regulator of circadian metabolism and has the potential for regulating obesity-related diseases. We examined whether circadian clock genes involving Clock/Bmal1 and the orphan nuclear receptor Shp (the small heterodimer partner) regulate the expression of Sglt1 to maintain glucose reabsorption and glucose homeostasis. Renal Sglt1 levels were increased in Clock-mutant or Bmal1-knockout (KO) mice and were decreased by activation of Bmal1 in an SHP-dependent manner. Mechanistically, the transactivation of Sglt1 by HNF1α (hepatic nuclear factor 1 alpha) was inhibited by SHP. In wild-type mice fed a western diet, activation of Shp by Nobiletin reduced Sglt1 levels and improved glucose reabsorption and glucose handling, but these beneficial effects were not seen in Clock−mutant and Bmal1 KO mice. These results demonstrate that normal inhibition of Sglt1 by Clock/Bmal1-SHP is defective in obesity, resulting in increased Sglt1 levels, glucose reabsorption, and renal steatosis. This Clock/Bmal1-SHP-Sglt1 pathway may present novel targets for treating obesity. This work was supported in part by National Institutes of Health (NIH) grant R56 HL137912 and American Heart Association Scientist Development Grant 2300158 and Grant-in-Aid 16GRNT30960027 to XP; by U.S. NIH grants DK121490, HL137202, HL158054 and HD094778, and VA Merit Award BX004113 to MMH; and NIH grants R01DK112042, R01HL142814, RF1AG061296, the UAB/UCSD O’Brien Center of Acute Kidney Injury NIH-P30DK079337, and the Department of Veterans Affairs to V Vallon. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.