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Sex-specific Effects of a2d-1 in the Ventromedial Hypothalamus of Female Mice
Controlling Glucose and Lipid Balance.
Authors Felsted JA, Meng A, Ameroso D, Rios M
Submitted By Submitted Externally on 9/28/2020
Status Published
Journal Endocrinology
Year 2020
Date Published 7/1/2020
Volume : Pages 161 : Not Specified
PubMed Reference 32337532
Abstract The thrombospondin receptor alpha2delta-1 (a2d-1) plays essential roles
promoting the activity of SF1 neurons in the ventromedial hypothalamus (VMH) and
mediating glucose and lipid metabolism in male mice. Its role in the VMH of
female mice remains to be defined, especially considering that this hypothalamic
region is sexually dimorphic. We found that a2d-1 depletion in SF1 neurons
differentially affects glucose and lipid balance control and sympathetic tone in
females compared to males. Mutant females show a modest increase in relative
body weight gain when fed a high-fat diet (HFD) and normal energy expenditure,
indicating that a2d-1 is not a critical regulator of energy balance in females,
similar to males. However, diminished a2d-1 function in the VMH leads to
enhanced glycemic control in females fed a chow diet, in contrast to the glucose
intolerance reported previously in mutant males. Interestingly, the effects of
a2d-1 on glucose balance in females are influenced by diet. Accordingly, females
but not males lacking a2d-1 exhibit diminished glycemic control as well as
susceptibility to hepatic steatosis when fed a HFD. Increased hepatic
sympathetic tone and CD36 mRNA expression and reduced adiponectin levels
underlie these diet-induced metabolic alterations in mutant females. The results
indicate that a2d-1 in VMH SF1 neurons critically regulates metabolic function
through sexually dimorphic mechanisms. These findings are clinically relevant
since metabolic alterations have been reported as a side effect in human
patients prescribed gabapentinoid drugs, known to inhibit a2d-1 function, for
the treatment of seizure disorders, neuropathic pain, and anxiety disorders.


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