{'fraction_non_alphanumeric': 0.03142748958727755, 'fraction_numerical': 0.02158273381294964, 'mean_word_length': 5.523456790123457, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
SPAK Kinase Modulates Energy Expenditure and Thermogenesis in Mice Fed a High‐fat Diet

Body weight regulation and glucose homeostasis are controlled by central and peripheral mechanisms. In the central nervous system, hypothalamic nuclei trough neuronal axes that release GABA modulate energy expenditure and thermogenesis and the peripheral glucose metabolism is controlled in part by pancreatic insulin secretion from β‐cells. Interestingly, the intracellular chloride concentration ([Cl−]i) is involved in the modulation of both processes, the GABA signaling and insulin secretion. The activity of the electroneutral cation coupled chloride cotransporters (CCC) is critical to define the [Cl−]i. Phosphorylation of the CCC members promotes Cl− influx, while dephosphorylation promotes Cl− efflux. The kinase that phosphorylates the CCCs is known as SPAK (STE20‐proline alanine rich kinase). The SPAK activity modulates the [Cl−]i by controlling the activity of the CCCs. In this regards, the homozygous SPAK‐Knockin mice lacking the threonine 243 of the T‐loop required for its activation (SPAKT243A/T243A) exhibit no SPAK activity and thus a marked decrease in CCCs phosphorylation. Here, to analyze the role of SPAK in metabolic homeostasis we fed wild type and SPAKT243A/T243A mice a high‐fat diet (HFD) for 17 weeks to evaluate weight gain, metabolic variables, energy expenditure, glucose tolerance, as well as, liver, pancreatic and adipose tissue histology and histochemistry. Food consumption was similar among groups during the feeding period. The wild type mice, however, gained 15.1 ± 0.8 g, whereas the SPAKT243A/T243A mice gained only 10.2 ± 2.0 g (p<0.01). At the end of the study, in contrast to wild type mice, SPAKT243A/T243A mice exhibited significantly lower fat mass, cholesterol, triglycerides and leptin levels, as well as improved insulin secretion and glucose tolerance. SPAKT243A/T243A mice did not develop hepatic steatosis and pancreatic islets hypertrophy as wild type did. The enhanced metabolic function of SPAKT243A/T243A mice was associated with increased whole body oxygen consumption and augmented fat oxidation. The molecular mechanisms responsible for this phenotype involve improved pancreatic β‐cell function, augmented skeletal muscle mitochondrial activity and increased brown adipose tissue UCP1‐mediated thermogenesis. Our data show that the absence of SPAK activity in mice is associated with an obesity resistant phenotype when exposed to HFD. These observations suggest that modulation of SPAK activity could be a potential new therapeutic avenue for obesity and glucose metabolism disorders.