Leptin affects body weight and reproduction mainly via receptors in the central nervous system. Different isoforms of the leptin receptor (leptin-R) exist, including a long isoform (leptin-R_L) with signalling capacity and short isoforms (leptin-R_S) with unknown function. The aim of this study was to examine leptin-R gene expression in different regions of the brain under conditions with altered body weight, in the female rat, including ovariectomy (OVX), oestradiol (E₂) treatment, fasting and a genetic model of obesity (Zucker fa/fa). Leptin-R gene expression was analysed by in situ hybridization using probes recognizing all receptor isoforms (leptin-R) or specifically leptin-R_L. Transcripts recognized by the leptin-R probe were abundant in the choroid plexus (CP), arcuate nucleus (ARC), ventromedial nucleus (VMN), thalamus (TH) and piriform cortex (PC). Leptin-R_L transcripts were detected in the ARC, VMN, TH and PC but not in the CP. Although no sex difference was observed, leptin-R gene expression was reduced by E₂ administration and increased by OVX. Administration of E₂ reduced leptin-R_L gene expression in the ARC and VMN but did not alter the expression in the TH or PC. OVX had no effect on the expression of leptin-R_L mRNA. Fasting also caused a differential regulation of leptin-R mRNAs, with an increase in abundance of leptin-R_L transcripts in the TH despite a decrease in leptin-R in this area. Obese Zucker rats had a similar pattern of expression with an increased expression of leptin-R_L transcripts in all brain areas analysed and a decrease in leptin-R gene expression. These results demonstrate a differential regulation of leptin-R_L and leptin-R_S which could provide a mechanism for regulating access to, and sensitivity of, discrete regions of the brain for circulating leptin. We suggest that fasting and E₂ alter the balance between leptin-R_L and leptin-R_S and that this could increase tissue sensitivity to leptin.

Summary Background Bariatric surgery in patients with obesity and type 2 diabetes is associated with diabetes remission and prevention of complications. The long-term effects of bariatric surgery on microvascular complications in patients with prediabetes are unknown. Methods The prospective, matched Swedish Obese Subjects study examines outcomes after bariatric surgery. Patients were recruited between September 1, 1987, and January 31, 2001. Age was 37–60 years and BMI was ≥34 kg/m2 in men and ≥38 kg/m2 in women. The surgery group (n=2010) underwent gastric bypass (13·2%), banding (18·7%), or vertical banded gastroplasty (68·1%), and controls (n=2037) received usual care. After exclusion of 4 patients with suspected type 1 diabetes, and 11 patients with unknown glucose status at baseline, 4032 of the 4047 participants in the SOS study were included in the current analysis. The main outcome of this report was incidence of microvascular events (retinopathy, diabetic kidney disease, and neuropathy, whichever came first), obtained from nationwide registers, in subgroups stratified by baseline glucose status (euglycemia n=2838; prediabetes n=591; screen-detected diabetes n=246; established diabetes n=357). Data were analyzed both by intention to treat and per protocol. Median follow-up was 19 years. This study is registered with ClinicalTrials.gov, NCT01479452. Findings There were 374 first-time microvascular events in the control group and 224 in the surgery group (hazard ratio, 0·56; 95% CI 0·48–0·66; p<0·0001). There was a significant interaction between baseline glucose status and treatment effect (p=0.0003), and unadjusted hazard ratios for comparing the surgery group to the control group were lowest in the subgroup with prediabetes (0·18; 95% CI 0·11–0·30), followed by subgroups with screen-detected diabetes (0·39; 95% CI 0·24–0·65), established diabetes (0·54; 95% CI 0·40–0·72), and euglycemia (0·63; 95% CI 0·48–0·81). In patients with baseline prediabetes, treatment was associated with reduced incidence of microvascular events both in those who developed diabetes and in those who remained diabetes free during follow-up. Interpretation Bariatric surgery was associated with reduced risk of microvascular complications in all subgroups, but the greatest relative risk reduction was observed in patients with baseline prediabetes. Our results indicate that prediabetes should be treated aggressively to prevent future microvascular events.

OBJECTIVE Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk for heart failure hospitalization potentially by inducing sodium excretion, osmotic diuresis, and plasma volume contraction. Few studies have investigated this hypothesis, but none have assessed cumulative sodium excretion with SGLT2 inhibition during standardized sodium intake in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS The DAPASALT trial was a mechanistic, nonrandomized, open-label study in patients with type 2 diabetes with preserved kidney function on a controlled standardized sodium diet (150 mmol/day). It evaluated the effects of dapagliflozin on sodium excretion, 24-h blood pressure, and extracellular, intracellular, and plasma volumes at the start of treatment (ST) (days 2–4), end of treatment (ET) (days 12–14), and follow-up (FU) (days 15–18). RESULTS Fourteen patients were included in the efficacy analysis. Mean (SD) baseline sodium excretion (150 [32] mmol/24-h) did not significantly change during treatment (change at ST: −7.0 mmol/24-h [95% CI −22.4, 8.4]; change at ET: 2.1 mmol/24-h [−28.8, 33.0]). Mean baseline 24-h systolic blood pressure was 128 (10) mmHg and significantly reduced at ST (−6.1 mmHg [−9.1, −3.1]; P &lt; 0.001) and ET (−7.2 mmHg [−10.0, −4.3]; P &lt; 0.001). Dapagliflozin did not significantly alter plasma volume or intracellular volume, while extracellular volume changed at ST (−0.7 L [−1.3, −0.1]; P = 0.02). As expected, 24-h urinary glucose excretion significantly increased during dapagliflozin treatment and reversed during FU. CONCLUSIONS During standardized sodium intake, dapagliflozin reduced blood pressure without clear changes in urinary sodium excretion, suggesting that factors other than natriuresis and volume changes may contribute to the blood pressure–lowering effects.

Objective. We explored the relationship between adiposity factors measured during mid-life and blood-brain barrier (BBB) integrity measured via the cerebrospinal fluid ⁄ serum (CSF ⁄ S) albumin ratio in late life. Adiposity factors included body mass index and blood levels of sex hormone binding globulin (SHBG) and leptin.Design. Retrospective analyses over 24 years within a longitudinal study.Setting. Population-based sample.Subjects. Eighty-one women. Main outcome measures. CSF ⁄ S albumin ratio.Results. The CSF ⁄ S albumin ratio measured at age 70-84 years was higher amongst women who were overweight or obese (6.50 ± 2.79 vs. 5.23 ± 1.61, age-adjusted P = 0.012), and was inversely correlated with SHBG (age-adjusted r = )0.321, P < 0.005) at age 46-60 years. In stepwise regression models, SHBG predicted the CSF ⁄ S albumin ratio (beta = )0.017, R 2 = 0.107, P = 0.007). The best model (R 2 = 0.187) predicting CSF ⁄ S albumin ratio included SHBG, age group (age 46 years versus >46), overweight or obesity, and an age group by SHBG interaction.Conclusions. Lower levels of SHBG in mid-life were related to worse BBB integrity in women after 24 years in late life, even considering other adiposity factors. SHBG may be important for understanding sex hormone-mediated mechanisms in brain health or as an independent marker of adipose tissue, the largest endocrine organ.