Correspondence matthias.betz@usb.ch (M.J.B.), irene.burger@usz.ch (I.A.B.), christian-wolfrum@ethz.ch (C.W.) In Brief Through genetic and pharmacological in vivo and in vitro approaches, Balaz et al. show that the mevalonate pathway is important for adipocyte browning. The importance of this pathway is supported by a retrospective clinical study and a small volunteer trial with fluvastatin. The authors identify geranylgeranyl pyrophosphate as the key mevalonate intermediate driving adipocyte browning. SUMMARYRecent research focusing on brown adipose tissue (BAT) function emphasizes its importance in systemic metabolic homeostasis. We show here that genetic and pharmacological inhibition of the mevalonate pathway leads to reduced human and mouse brown adipocyte function in vitro and impaired adipose tissue browning in vivo. A retrospective analysis of a large patient cohort suggests an inverse correlation between statin use and active BAT in humans, while we show in a prospective clinical trial that fluvastatin reduces thermogenic gene expression in human BAT. We identify geranylgeranyl pyrophosphate as the key mevalonate pathway intermediate driving adipocyte browning in vitro and in vivo, whose effects are mediated by geranylgeranyltransferases (GGTases), enzymes catalyzing geranylgeranylation of small GTP-binding proteins, thereby regulating YAP1/TAZ signaling through F-actin modulation. Conversely, adipocyte-specific ablation of GGTase I leads to impaired adipocyte browning, reduced energy expenditure, and glucose intolerance under obesogenic conditions, highlighting the importance of this pathway in modu-lating brown adipocyte functionality and systemic metabolism.

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Objectives: We aimed to explore the impact of the Swiss shutdown in spring 2020 on the intensity of health services use in general practice.Methods: Based on an electronic medical records database, we built one patient cohort each for January-June 2019 (control, 173,523 patients) and 2020 (179,086 patients). We used linear regression to model weekly consultation counts and blood pressure (BP) and glycated hemoglobin (HbA1c) measurement counts per 100 patients and predicted non-shutdown values. Analyses were repeated for selected at-risk groups and different age groups.Results: During the shutdown, weekly consultation counts were lower than predicted by −17.2% (total population), −16.5% (patients with hypertension), −17.5% (diabetes), −17.6% (cardiovascular disease), −15.7% (patients aged <60 years), −20.4% (60–80 years), and −14.5% (>80 years). Weekly BP counts were reduced by −35.3% (total population) and −35.0% (hypertension), and HbA1c counts by −33.2% (total population) and −29.8% (diabetes). p-values <0.001 for all reported estimates.Conclusion: Our results document consequential decreases in consultation counts and chronic disease monitoring during the shutdown. It is crucial that health systems remain able to meet non-COVID-19-related health care needs.

Aims/hypothesisIn the context of diabetes, the health benefit of antioxidant treatment has been widely debated. In this study, we investigated the effect of antioxidant treatment during the development of insulin resistance and hyperphagia in obesity and partial lipodystrophy.MethodsWe studied the role of antioxidants in the regulation of insulin resistance using the tamoxifen-inducible fat-specific insulin receptor knockout (iFIRKO) mouse model, which allowed us to analyse the antioxidant’s effect in a time-resolved manner. In addition, leptin-deficient ob/ob mice were used as a hyperphagic, chronically obese and diabetic mouse model to validate the beneficial effect of antioxidants on metabolism.ResultsAcute induction of insulin receptor knockout in adipocytes changed the substrate preference to fat before induction of a diabetic phenotype including hyperinsulinaemia and hyperglycaemia. In healthy chow-fed animals as well as in morbidly obese mice, this diabetic phase could be reversed within a few weeks. Furthermore, after the induction of insulin receptor knockout in mature adipocytes, iFIRKO mice were protected from subsequent obesity development through high-fat diet feeding. By genetic tracing we show that the persistent fat mass loss in mice after insulin receptor knockout in adipocytes is not caused by the depletion of adipocytes. Treatment of iFIRKO mice with antioxidants postponed and reduced hyperglycaemia by increasing insulin sensitivity. In ob/ob mice, antioxidants rescued both hyperglycaemia and hyperphagia.Conclusions/interpretationWe conclude that fat mass reduction through insulin resistance in adipocytes is not reversible. Furthermore, it seems unlikely that adipocytes undergo apoptosis during the process of extreme lipolysis, as a consequence of insulin resistance. Antioxidants have a beneficial health effect not only during the acute phase of diabetes development, but also in a temporary fashion once chronic obesity and diabetes have been established.Electronic supplementary materialThe online version of this article (10.1007/s00125-019-4937-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.