Highlights
- •Ovarian insufficiency (OVX) increases body weight and SPTLC1/SPTLC2 expression in hypothalamus
- •Down-regulation of hypothalamic SPTLC1 decreases neuronal inflammation
- •Down-regulation of hypothalamic SPTLC1 partially reverses glucose intolerance induced by OVX
- •Down-regulation of hypothalamic SPTLC1 represses the second phase of insulin secretion induced by OVX
- •Down-regulation of hypothalamic SPTLC1 reverses the defect of glucose-induced insulin secretion induced by OVX
Abstract
Oestrogens regulate body weight through their action on hypothalamus to modulate food
intake and energy expenditure. Hypothalamic de novo ceramide synthesis plays a central
role on obesity induced by oestrogen deficiency. Depletion in oestrogens is also known
to be associated with glucose intolerance, which favours type 2 diabetes (T2D). However,
the implication of hypothalamic ceramide in the regulation of glucose homeostasis
by oestrogen is unknown. Here, we studied glucose homeostasis and insulin secretion
in ovariectomized (OVX) female rats. OVX induces body weight gain associated with
a hypothalamic inflammation and impaired glucose homeostasis. Genetic blockade of
ceramide synthesis in the ventromedial nucleus of the hypothalamus (VMH) reverses
hypothalamic inflammation and partly restored glucose tolerance induced by OVX. Furthermore,
glucose-stimulated insulin secretion (GSIS) is increased in OVX rats due to a raise
of insulin secretion second phase, a characteristic of early stage of T2D. In contrast,
GSIS from isolated islets of OVX rats is totally blunted. Inhibition of ceramide synthesis
in the VMH restores GSIS from isolated OVX islets and represses the second phase of
insulin secretion. Stimulation of oestrogen receptor α (ERα) by oestradiol (E2) down-regulates
ceramide synthesis in hypothalamic neuronal GT1–7 cells but no in microglial SIM-A9
cells. In contrast, genetic inactivation of ERα in VMH upregulates ceramide synthesis.
These results indicate that hypothalamic neuronal de novo ceramide synthesis triggers
the OVX-dependent impairment of glucose homeostasis which is partly mediated by a
dysregulation of GSIS.
Keywords
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Article info
Publication history
Published online: August 06, 2021
Accepted:
August 2,
2021
Received:
March 22,
2021
Identification
Copyright
© 2021 Elsevier Inc. All rights reserved.
