Energy imbalance alters Ca2+ handling and excitability of POMC neurons

Abstract

Satiety-signaling, pro-opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus play a pivotal role in the regulation of energy homeostasis. Recent studies reported altered mitochondrial dynamics and decreased mitochondria- endoplasmic reticulum contacts in POMC neurons during diet-induced obesity. Since mitochondria play a crucial role in Ca2+ signaling, we investigated whether obesity alters Ca2+ handling of these neurons in mice. In diet-induced obesity, cellular Ca2+ handling properties including mitochondrial Ca2+ uptake capacity are impaired, and an increased resting level of free intracellular Ca2+ is accompanied by a marked decrease in neuronal excitability. Experimentally increasing or decreasing intracellular Ca2+ concentrations reproduced electrophysiological properties observed in diet-induced obesity. Taken together, we provide the first direct evidence for a diet-dependent deterioration of Ca2+ homeostasis in POMC neurons during obesity development resulting in impaired function of these critical energy homeostasis-regulating neurons.DOI: http://dx.doi.org/10.7554/eLife.25641.001

Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity

“…Interestingly, AIF deficiency resulted in reduced spontaneous firing of action potentials in POMC neurons from NCD-fed mice (Figures 3A and 3A1). In line with previous reports (Diano et al, 2011; Jo et al, 2009; Paeger et al, 2017), HFD feeding strongly impaired POMC neuron firing activity in control mice (Figures 3B and 3B1), which was attenuated in HFD-fed AIF ΔPOMC mice (Figures 3B and 3B1). …”

“…Upon high-fat diet (HFD) feeding, mitochondrial network complexity and dynamics are impaired in POMC neurons (Diano et al, 2011; Schneeberger et al, 2013), causing deterioration of mitochondrial Ca 2+ handling and decreased excitability in these neurons (Paeger et al, 2017). The expression of mitofusin 2 (MFN2), an ubiquitously expressed mitochondrial transmembrane dynamin-like GTPase protein mediating mitochondrial fusion processes (Chen et al, 2003) and mitochondrial-ER interactions (de Brito and Scorrano, 2008), is reduced in the hypothalamus as early as 4 days after beginning of a HFD feeding, and deletion of MFN2 specifically in POMC neurons results in increased body weight gain due to enhanced food intake as well as reduced energy expenditure (EE) and BAT thermogenesis (Schneeberger et al, 2013).…”

Plasticity of calcium-permeable AMPA glutamate receptors in Pro-opiomelanocortin neurons

“…The modulation of glutamate receptor structure has been shown to be a key part of neuronal responses to changes in the external environment, including learning, memory, and drug addition. Because our observations emphasize the importance of calcium entry into POMC neurons during their activation, our results provide a feasible mechanistic explanation for long-term impairment of POMC neuronal functions on HFD in relation to calcium overload ( Paeger et al, 2017 ).…”

Mitochondrial Dynamics in the Brain Are Associated With Feeding, Glucose Homeostasis, and Whole-Body Metabolism

“…HFD decreases spontaneous activity and hyperpolarizes the membrane potential of POMC neurons (68,132). Glucose responsiveness by POMC neurons is also abolished in obese mice following a HFD, which is linked to an increase in the mitochondrial protein UCP2.…”

“…In DIO mice downregulation of Mfn2 alters mitochondrial network dynamics, reduces mitochondria-ER contacts, and impairs intracellular Ca 2+ -handling (64,68). Ablation of Mfn1 in POMC neurons in mice led to defective mitochondrial architecture remodeling following feeding (65).…”