Weight gain is an undesirable side-effect of long-term lithium administration which notably interferes with treatment compliance. The mechanisms of this weight gain remain unclear, making its management in patients difficult. In this paper, studies describing the features of this weight gain in patients and in rats treated with chronic lithium administration are reviewed. The effects of lithium on body weight differ between patients and rats in a number of ways, including the observation that excessive weight gain is observed in both male and female patients, but only in female rats. Nevertheless, an animal model of lithium-induced weight gain may be able to provide useful insights into some of the specific mechanisms involved, particularly those related to interactions with gonadal steroid function. We discuss the effects of lithium on the endocrine system, neurotransmitters, metabolism, electrolyte regulation, and feeding behavior, which might underlie lithium's effects on body weight. Finally, suggestions for the management of weight gain in the clinical setting are presented. These include, in the long term, dietary control and physical activity and, in the short term, choosing among several drugs that have been tested either in patients or in animal models of obesity. If weight gain still cannot be controlled and treatment compliance is at risk, the mood stabilizers carbamazepine or valproic acid might be substituted for lithium treatment.

Aims Obesity, diabetes and metabolic syndromes are risk factors of atrial fibrillation (AF). We tested the hypothesis that metabolic disorders have a direct impact on the atria favoring the formation of the substrate of AF. Methods & Results Untargeted metabolomic and lipidomic analysis was used to investigate the consequences of a prolonged high fat diet (HFD) on mouse atria. Atrial properties were characterized by measuring mitochondria respiration in saponin-permeabilized trabeculae, by recording action potential with glass microelectrodes in trabeculae and ionic currents in myocytes using the perforated configuration of patch clamp technique and by several immuno-histological and biochemical approaches. After 16 weeks of HFD, obesogenic mice showed a vulnerability to AF. The atrial myocardium acquired an adipogenic and inflammatory phenotypes. Metabolomic and lipidomic analysis revealed a profound transformation of atrial energy metabolism with a predominance of long-chain lipid accumulation and beta-oxidation activation in the obese mice. Mitochondria respiration showed an increased use of palmitoyl-CoA as energy substrate. Action potentials were short duration and sensitive to the K-ATP-dependent channel inhibitor, whereas K-ATP current was enhanced in isolated atrial myocytes of obese mouse. Conclusion HFD transforms energy metabolism, causes fat accumulation, and induces electrical remodeling of the atrial myocardium of mice that become vulnerable to AF. Translational perspective Understanding the link between metabolic diseases and atrial fibrillation is of major importance. One hypothesis claims that, in addition to shared co-morbidities, metabolic disorders favor the substrate of atrial fibrillation. Here we show that after prolonged high fat diet, the atrial myocardium becomes adipogenic, inflamed and vulnerable to atrial fibrillation. This tissue remodeling appears to result from an unbalance between uptake and oxidation of fatty acid resulting in long-chain lipid storage, activation of metabolic-sensitive potassium channels and action potential shortening. Therefore, diet appears to be an important link between metabolic disorders and atrial fibrillation.

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