Dexamethasone Alters the Appetite Regulation via Induction of Hypothalamic Insulin Resistance in Rat Brain.
Elevated levels of glucocorticoid, a steroid hormone released in response to stress, have been implicated in the pathophysiology of diabetes, which is now known to extend its effect on brain functions. Hence, we aimed to investigate the status of brain insulin signaling in response to dexamethasone (a synthetic glucocorticoid) treatment in female Charles Foster rat. This model exhibited pronounced hyperinsulinemia and glucose intolerance with loss in appetite and body weight. Immunoblotting of insulin receptor (INSR)-PI3kinase-AKT demonstrated reduced insulin signaling in hypothalamus but no change in hippocampus, cortex, and cerebellum in dexamethasone-treated rats as compared to vehicle-treated rats, signifying the diversity of distribution and function of insulin in different brain regions. These results also correlated with appetite change, a key function governed by hypothalamus. Hence, we further explored the hypothalamic feeding circuit and found altered levels of neuropeptide genes (Agrp, Npy, Pomc) and candidate nutrient sensors (GLUT1, SirT1, and PPARγ). There was also a considerable reduction in glycogen content and appetite-regulating neurotransmitters (GABA, glutamate, dopamine) in dexamethasone-treated rats. Thus, concluding that dexamethasone not only induces peripheral insulin resistance but also impairs hypothalamic function of appetite regulation via the interwoven cascade of insulin signaling, neurotransmitters, and neuropeptides. Graphical Abstract Reduced insulin signaling as well as elevated glucocorticoid levels in hypothalamus modulates the key appetite regulating neuropeptides, neurotransmitters, and nutrient sensors resulting into reduced appetite and bodyweight.
Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India.
Ragitha
R
Chruvattil
Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India.
Shreya
S
Banerjee
Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India.
Sarmi
S
Nath
Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India.
Jatin
J
Machhi
Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India.|ICMR Headquarters, Ansari Nagar, New Delhi, Delhi-110029, India.
Gitika
G
Kharkwal
Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India.
Mange Ram
MR
Yadav
Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India. sglmescrl@gmail.com.
Sarita
S
Gupta
D000818:Animals; D001069:Appetite Regulation / Q000187:drug effects / Q000502:physiology*; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology*; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism; D051381:Rats
D005938:Glucocorticoids; D003907:Dexamethasone
Anorexigenic neuropeptides; Brain insulin signaling; Glycogen; Hypothalamus; Neurotransmitters; Orexigenic neuropeptides