Weight is defended so that increases or decreases in body mass elicit responses that favor restoration of one's previous weight. While much is known about the signals that respond to weight loss and the central role that leptin plays, the lack of experimental systems studying the overfed state has meant little is known about pathways defending against weight gain. We developed a system to study this physiology and found that overfed mice defend against increased weight gain with graded anorexia but, unlike weight loss, this response is independent of circulating leptin concentration. In overfed mice that are unresponsive to orexigenic stimuli, adipose tissue is transcriptionally and immunologically distinct from fat of ad libitum-fed obese animals. These findings provide evidence that overfeeding-induced obesity alters adipose tissue and central responses in ways that are distinct from ad libitum obesity and activates a non-leptin system to defend against weight gain.

Regulation of blood pH-critical for virtually every facet of life-requires that the renal proximal tubule (PT) adjust its rate of H(+) secretion (nearly the same as the rate of HCO3 (-) reabsorption, JHCO3 ) in response to changes in blood [CO2] and [HCO3 (-)]. Yet CO2/HCO3 (-) sensing mechanisms remain poorly characterized. Because receptor tyrosine kinase inhibitors render JHCO3 in the PT insensitive to changes in CO2 concentration, we hypothesized that the structural features of receptor protein tyrosine phosphatase-γ (RPTPγ) that are consistent with binding of extracellular CO2 or HCO3 (-) facilitate monitoring of blood CO2/HCO3 (-) concentrations. We now report that PTs express RPTPγ on blood-facing membranes. Moreover, RPTPγ deletion in mice eliminated the CO2 and HCO3 (-) sensitivities of JHCO3 as well as the normal defense of blood pH during whole-body acidosis. Thus, RPTPγ appears to be a novel extracellular CO2/HCO3 (-) sensor critical for pH homeostasis.

The water channel Aquaporin 1 (AQP1) is widely expressed throughout the body. Our lab demonstrated that AQP1 also can act as a CO2 channel when heterologously expressed in oocytes or when studied in the intact proximal tubule. We hypothesized that AQP1 plays a physiologically important role in O2 transport. Because AQP1 is present at high levels in erythrocytes and the pulmonary capillary endothelium, we compared voluntary wheel running over a 24‐h period in AQP1‐null vs wild‐type mice under conditions of hypoxia (ambient [O2] = 16%), normoxia (21%), and hyperoxia (40%). For wild‐type mice, the distances run were 16%: 9.2 ± 0.5 km (n = 28), 21%: 10.7 ± 0.5 km (n = 37), and 40%: 12.1 ± 0.6 km (n = 21). For AQP1‐null mice, the distances were 16%: 4.7 ± 0.5 km (n = 8), 21%: 6.2 ± 0.6 km (n = 13), and 40%: 6.9 ± 0.6 km (n = 12). We performed a linear‐regression analysis of distance run as a function of AQP1 status and [O2], treating [O2] categorically in reference to 21% O2. The AQP1 knockout reduced the distance run by 4.7 ± 0.5 km (p < 0.001), adjusting for [O2]. Compared to 21% O2, reducing [O2] to 16% reduced the distance run by 1.6 ± 0.6 km (p = 0.01), whereas increasing [O2] to 40% increased the distance run by 1.2 ± 0.6 km (p = 0.04), adjusting for AQP1 status. Thus, AQP1‐null mice have a major defect in voluntary exercise tolerance, consistent with the hypothesis that AQP1 plays an important physiological role in O2 transport across plasma membranes.