mGluR5 functionally interacts with estrogen receptors and is required in the female ventromedial hypothalamus for the regulation of glucose and lipid homeostasis
metabolic syndrome, characterized by dysregulated glycemic control and lipid metabolism,
disproportionately affects postmenopausal women and is a major public health concern.
The central mechanisms governing peripheral glucose and lipid homeostasis and the role
of estrogens in these systems are poorly understood. Previous investigations
demonstrated that brain-derived neurotroph... read moreic factor (BDNF) in the ventromedial
hypothalamus (VMH) is a critical regulator of energy and glucose metabolism. We found
that metabotropic glutamate receptor subtype 5 (mGluR5) was markedly reduced in the VMH
of mutant mice with global BDNF depletion. Thus, we hypothesize that mGluR5 may be
acting within this nucleus to mediate energy and glucose balance. We show that mGluR5 in
steroidogenic factor-1 (SF1)+ neurons, which are exclusive to the VMH, serves an
essential and sex-specific role in glycemic control and lipid metabolism. Accordingly,
female but not male mice with mGluR5 deletion in SF1+ neurons (mGluR52L/2L:SF1-cre)
exhibit severe glucose intolerance, insulin resistance and triglyceride accumulation in
white adipose tissue accompanied by adipocyte hypertrophy. Reduced excitability of SF1+
neurons and diminished sympathetic tone was observed exclusively in mGluR52L/2L:SF1-cre
females and underlie these metabolic alterations. Moreover, sex-specific effects of
mGluR5 are explained by its necessity in mediating the beneficial effects of estrogen
receptor-α (ERα) signaling on glucose balance control in females.
Collectively, these findings inform a novel and critical synergism between mGluR5 and
estrogen receptors in the control of VMH neuronal activity, glucose homeostasis and
lipid metabolism. These results are significant as central mechanisms predisposing
estrogen deficient postmenopausal women to increased risk of metabolic symptoms remain
Thesis (Ph.D.)--Tufts University, 2017.
Submitted to the Dept. of Neuroscience.
Advisor: Maribel Rios.
Committee: Jamie Maguire, and Peter Juo.
Keyword: Neurosciences.read less