A glucose-stimulated BOLD fMRI study of hypothalamic dysfunction in mice fed a high-fat and high-sucrose diet

Abstract

Running headline: Hypothalamic fMRI in diet-induced obese miceAbbreviations: AgRP, agouti-related peptide; AMPK, AMP-activated protein kinase; ARC, arcuate nucleus; BOLD, blood oxygen level-dependent; CART, cocaine and amphetamine regulated transcript; CREB, cAMP response element-binding protein; DMN, dorsomedial nucleus; fMRI, functional magnetic resonance imaging; FOV, field of view; LH, lateral hypothalamus; MC4R, melanocortin 4 receptor; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; PVN, paraventricular nucleus; T2D, type 2 diabetes; TE, echo time; TR, repetition time; VMN, ventromedial nucleus; VOI, volume of interest. AbstractThe hypothalamus is the central regulator of energy homeostasis. Hypothalamic neuronal circuits are disrupted upon overfeeding, and play a role in the development of metabolic disorders.While mouse models have been extensively employed for understanding mechanisms of hypothalamic dysfunction, functional magnetic resonance imaging (fMRI) on hypothalamic nuclei has been challenging. We implemented a robust glucose-induced fMRI paradigm that allows to repeatedly investigate hypothalamic responses to glucose. This approach was used to test the hypothesis that hypothalamic nuclei functioning is impaired in mice exposed to a high-fat and highsucrose diet (HFHSD) for 7 days. The blood oxygen level-dependent (BOLD) fMRI signal was measured from brains of mice under light isoflurane anaesthesia, during which a 2.6 g/kg glucose load was administered. The mouse hypothalamus responded to glucose but not saline administration with a biphasic BOLD fMRI signal reduction. Relative to controls, HFHSD-fed mice showed attenuated or blunted responses in arcuate nucleus, lateral hypothalamus, ventromedial nucleus and dorsomedial nucleus, but not in paraventricular nucleus. In sum, we have developed an fMRI paradigm that is able to determine dysfunction of glucose-sensing neuronal circuits within the mouse hypothalamus in a non-invasive manner.

Telmisartan prevents high-fat diet-induced neurovascular impairments and reduces anxiety-like behavior

“…Other studies have shown before that the chronic consumption of high fat diets leads to obesity and negatively affects brain function in terms of a worsen outcome after ischemic stroke 41 and that short-term high-fat and high-sucrose feeding impairs hypothalamic neuronal circuits, particularly in the arcuate, the ventromedial and the dorsomedial nucleus. 42 Visa versa, short-term exercise training effectively decreases insulin-stimulated brain glucose uptake in sedentary subjects with insulin resistance. 43…”

Hormone-sensitive lipase is localized at synapses and is necessary for normal memory functioning in mice

“…Mice were anaesthetized with isoflurane and quickly decapitated, and brains were dissected, frozen in N2 (l) and stored at -80 °C until further experiments. For immunofluorescence experiments, mice under isoflurane anaesthesia were sacrificed by cardiac perfusion with cold PBS and then cold phosphate-buffered formaldehyde (Histolab, Askim, Sweden), and brains were processed as detailed previously (22).…”