Excess consumption of carbohydrates, fat and calories leads to non-alcoholic fatty liver disease (NAFLD) and hepatic insulin resistance; these are major factors in the pathogenesis of type II diabetes. Hormones and catecholamines acting through G-protein coupled receptors (GPCRs) linked to phospholipase C (PLC) and increases in cytosolic Ca²⁺ ([Ca²⁺ ]_c ) regulate many metabolic functions of the liver. In the intact liver, catabolic hormones such as glucagon, catecholamines and vasopressin integrate and synergize to regulate the frequency and extent to which [Ca²⁺ ]_c waves propagate across hepatic lobules to control metabolism. Dysregulation of hepatic Ca²⁺ homeostasis has been implicated in the development of metabolic disease, but changes in hepatic GPCR-dependent Ca²⁺ signalling have been largely unexplored in this context. We show that short-term, 1-week, high-fat diet (HFD) feeding of mice attenuates noradrenaline-stimulated Ca²⁺ signalling, reducing the number of cells responding and suppressing the frequency of [Ca²⁺ ]_c oscillations in both isolated hepatocytes and intact liver. The 1-week HFD feeding paradigm did not change basal Ca²⁺ homeostasis; endoplasmic reticulum Ca²⁺ load, store-operated Ca²⁺ entry and plasma membrane Ca²⁺ pump activity were unchanged compared to low-fat diet (LFD)-fed controls. However, noradrenaline-induced inositol 1,4,5-trisphosphate production was significantly reduced after HFD feeding, demonstrating an effect of HFD on receptor-stimulated PLC activity. Thus, we have identified a lesion in the PLC signalling pathway induced by short-term HFD feeding, which interferes with hormonal Ca²⁺ signalling in isolated hepatocytes and the intact liver. These early events may drive adaptive changes in signalling, which lead to pathological consequences in fatty liver disease. KEY POINTS: Non-alcoholic fatty liver disease (NAFLD) is a growing epidemic. In healthy liver, the counteracting effects of catabolic and anabolic hormones regulate metabolism and energy storage as fat. Hormones and catecholamines promote catabolic metabolism via increases in cytosolic Ca²⁺ ([Ca²⁺ ]_c ). We show that 1 week high-fat diet (HFD) feeding of mice attenuated the Ca²⁺ signals induced by physiological concentrations of noradrenaline. Specifically, HFD suppressed the normal pattern of periodic [Ca²⁺ ]_c oscillations in isolated hepatocytes and disrupted the propagation of intralobular [Ca²⁺ ]_c waves in the intact perfused liver. Short-term HFD inhibited noradrenaline-induced inositol 1,4,5-trisphosphate generation, but did not change basal endoplasmic reticulum Ca²⁺ load or plasma membrane Ca²⁺ fluxes. We propose that impaired Ca²⁺ signalling plays a key role in the earliest phases of the etiology of NAFLD, and is responsible for many of the ensuing metabolic and related dysfunctional outcomes at the cellular and whole tissue level.

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