Table 1.

Targeting hypothalamic inflammation in preclinical disease models

Experimental models (animal/tissue)	Treatment/strategy	Effects	References
C57BL/6, HFD	PLX5622 (a CSF1R inhibitor) Oral route	Depletes microglia in MBH, reduces weight gain, total body fat, and food intake	[113]
Hypothalamic slice culture	Liposomal clodronate treatment	Depletes microglia, abolishes palmitic acid-induced M1 cytokine secretion	[41]
DTRBMT mice (C57BL/6, SFA gavage with clarified milk fat, coconut oil)	Ki20227, PLX5622 (CSF1R inhibitors) Oral route	Depletes microglia in the hypothalamus, enhances leptin-induced STAT3 activation by ARC neurons, decreases food intake	[41]
C57BL/6J, HFD	Arabinofuranosyl cytidine (a mitotic inhibitor) Infusion into the lateral ventricle	Inhibits microglial proliferation in ARC, inhibits excessive calorie intake and body weight gain, restores hypothalamic leptin sensitivity, and decreases peripheral inflammation	[110]
C57BL/6J, HFD	Butein icv route	Inhibits hypothalamic IKKβ/NF-κB signaling, improves glucose homeostasis	[375]
C57BL/6J, HFD	ARC-directed injection of AAV2-IκBα-mt	Overexpresses IκBα-mt in the ARC, attenuates diet-induced obesity, improves glucose homeostasis	[375]
IKKβMGKO mice, HFD	Microglia-specific deletion of Ikbkb	Reduces food intake, decreases weight gain	[113]
Male Wistar rats, HFD	Antibody against TLR4 Infliximab (antibody against TNF-α) icv route	Reduces hypothalamic resistance to leptin, improves insulin signal transduction in the liver, reduces liver steatosis	[27]
C57BL/6 J, HFD	LKB1 overexpression in hypothalamus	Inhibits hypothalamic inflammation, inhibits food intake and body weight gain, improves glucose tolerance, and insulin sensitivity	[387]
4‐1BB‐deficient mice (C57BL/6 J background), HFD; glial cell culture	TKS‐1 treatment (a neutralizing antibody that interrupts interaction between 4-1BBL and 4-1BB)	Reduces hypothalamic inflammation	[330]
C57BL/6 J mice, HFD	Epigallocatechin-3-gallate Oral route	Attenuates hypothalamic inflammation and microglial overactivation, inhibits diet-induced obesity, and enhances BAT thermogenesis	[383]
Wistar rats	Minocycline Intraperitoneal (ip) route	Reverses the effect of a neonatal overfeeding-induced increase in microglial numbers	[373]
Swiss mice, HFD	Flax seed oil, olive oil Oral route	Reduces diet-induced hypothalamic inflammation, reduces food intake and body-mass gain, and improves insulin action and glucose homeostasis	[67]
Wistar rats, HFD	α-Linolenic, oleic acid icv route	Reduces hypothalamic inflammation and expression of the apoptotic protein	[67]
C57B/L6 mice, HFD	Beta-aminoisobutyric acid Oral route	Reduces microglial activation and hypothalamic inflammation and may affect obesity pathogenesis	[382]
B6/SJL mice, HFD	Quercetin Oral route	Reduces microglial activation and inflammatory cytokines in the hypothalamus, attenuates neuronal damage markers	[384]
C57B/L6 mice, HFD	Filbertone Oral route	Reduces HFD-induced microglial activation, inhibits MAPK and NF-κB pathways, and protects from obesity-induced hypothalamic inflammation	[381]
C57B/L6 mice, STZ	AZD7545 (a PDK2 inhibitor) Oxamate (an LDH inhibitor) GSK2837808 (an LDH inhibitor) Ki20227 (a CSF1R inhibitor) Bay 11–7085 (an inhibitor of I-κB phosphorylation) icv route	Attenuates diabetes-induced gliosis, inflammatory cytokines and lactic acid production in the hypothalamus, attenuates diabetes-induced increase in food intake	[28]
SHR rats (Spontaneously hypertensive rats)	Tetracycline-3 (CMT3) icv route	Reduces the microglial number, activation, and proinflammatory cytokine production in the PVN, decreases mean arterial pressure, normalizes sympathetic activity, and left ventricular hypertrophy	[257]
Sprague–Dawley rats (s.c. infusion of Ang II)	Minocycline icv route	Reduces the microglial number and inflammatory cytokines in PVN, attenuates Ang II-induced hypertension	[215]
SHR rats (Spontaneously hypertensive rats)	Aerobic training	Decreases microglia activation, inhibits proinflammatory cytokines expression in PVN, and improves autonomic dysfunction associated with hypertension	[372]
SHR rats (Spontaneously hypertensive rats)	L-798106 [E3-class prostanoid (EP3) receptor inhibitor] infusion into PVN	Attenuates ROS and proinflammatory cytokines in the PVN, ameliorates hypertension and cardiac hypertrophy	[212]
Dahl salt-sensitive (S) rats	Pyrrolidine dithiocarbamate (a selective NF-κB inhibitor) Bilateral infusion into PVN	Inhibits NF-κB activity in PVN, attenuates NLRP3, IL-1β, and oxidative stress in the PVN, decreases hypertension	[378]
SHR rats (Spontaneously hypertensive rats)	Pentoxifylline, Etanercept (TNF-α blockers) Bilateral infusion into PVN	Attenuates PVN NF-κB p65 activity and oxidative stress, attenuates hypertension-induced sympathetic hyperactivity and cardiac hypertrophy	[380]
Dahl salt-sensitive (S) rats (High-salt diet)	PD98059 (a p44/42 MAPK inhibitor) Bilateral infusion into PVN	Attenuates oxidative stress, modulates neurotransmitters, and decreases hypertension	[388]
C57BL/6 mice (HFD)	MBH-directed viral delivery of dominant-negative IκBα (IκBαDN)	Suppresses NF-κB in the hypothalamus and reduces obesity-related hypertension	[18]
shRNA (VEGF)GFAP/+ mice, HFHS diet (C57BL/6 J background)	shRNA-mediated knockdown of Vegfa mRNA in astrocytes	Inhibits astrocyte VEGF, reduces sympathetic hyperactivity, and prevents obesity-induced hypertension	[236]
MBH-IκBα mice (C57BL/6 mice background)	MBH-directed lentiviral gene delivery of dominant-negative IκBα (IκBαDN)	Improves cognition, attenuates aging-related muscle weakness, and decreases aging-related biomarkers	[236]
Ames dwarf mice, Snell dwarf, and GHR−/− mice	Low growth hormone (GH) action	Lowers hypothalamic inflammation, extension of lifespan	[385]
UM-HET3 mice	Calorie restriction	Reduces reactive gliosis associated with aging, reduces TNF-α production in microglial cells	[386]
UM-HET3 mice	Acarbose, 17-α-estradiol, nordihydroguaiaretic acid Oral route	Reduces microglial activation and inflammatory response in the hypothalamus of old mice	[101, 102]

HFD high-fat diet, HFHS high-fat high sucrose, SFAs saturated fatty acid, icv intracerebroventricular, sc subcutaneous, PVN paraventricular nucleus, MBH mediobasal hypothalamus, ARC arcuate nucleus, GH growth hormone, GHR growth hormone receptor, VEGF vascular endothelial growth factor, BAT brown adipose tissue, STZ streptozotocin, CSF1R colony-stimulating factor 1 receptor, LDH lactate dehydrogenase, PDK2 pyruvate dehydrogenase kinase, LKB1 liver kinase B1, TLR4 toll-like receptor 4