The gut microbiota regulates hypothalamic inflammation and leptin sensitivity in Western diet-fed mice via a GLP-1R-dependent mechanism

Abstract

Mice lacking a microbiota are protected from diet-induced obesity. Previous studies have shown that feeding a Western diet causes hypothalamic inflammation, which in turn can lead to leptin resistance and weight gain. Here, we show that wild-type (WT) mice with depleted gut microbiota, i.e., germ-free (GF) and antibiotic-treated mice, have elevated levels of glucagon-like peptide-1 (GLP-1), are protected against diet-induced hypothalamic inflammation, and have enhanced leptin sensitivity when fed a Western diet. Using GLP-1 receptor (GLP-1R)deficient mice and pharmacological inhibition of the GLP-1R in WT mice, we demonstrate that intact GLP-1R signaling is required for preventing hypothalamic inflammation and enhancing leptin sensitivity. Furthermore, we show that astrocytes express the GLP-1R, and deletion of the receptor in glial fibrillary acidic protein (GFAP)-expressing cells diminished the antibiotic-induced protection against diet-induced hypothalamic inflammation. Collectively, our results suggest that depletion of the gut microbiota attenuates diet-induced hypothalamic inflammation and enhances leptin sensitivity via GLP-1R-dependent mechanisms.

Pharmacological blockade of the EP3 prostaglandin E2 receptor in the setting of type 2 diabetes enhances β-cell proliferation and identity and relieves oxidative damage

“…EP3 blockade increased the overall Nrf2 protein signal in db/+ and db/db mice, and significantly increased the nuclear localization of Nrf2 in db/db mice ( Figure 6 A–A'). Analysis of the RNA-Seq data showed a strong upregulation of a set of canonical Nrf2 target genes ( Figure 6 C), including those with antioxidant functions ( Nqo1, Txn1, Gsr, Gclc, Gstm1 ), those involved in iron metabolism ( Ftl1 and Fth1 ), and those that produce NADPH ( Me1, G6pdx, Idh1 ) [ 17 ], while the expression of Keap1 , a negative regulator of Nrf2 [ 20 ], was decreased. In addition, the levels of 8-hydroxydeoxyguanosine (8OHdG), a marker of DNA damage, were significantly decreased in both db/+ and db/db mice after DG-041 treatment ( Figure 7 A–B).…”

“…Sections were rehydrated and subjected to sodium-citrate-induced antigen retrieval. The primary antibodies used were: guinea pig anti-insulin (1:400; Dako #A0564, Carpinteria, CA), mouse anti-glucagon (1:500; EMD Millipore #MABN238, Bellerica, MA), rabbit anti-Ki67 (1:500; Abcam #ab15580, Cambridge, MA), rabbit anti-GLP-1R (1:500; Abcam #ab218532, validated on Glp1−/− tissue in [ 20 ]), or mouse anti-GLP-1R (1:30, DHSB mAb #7F38, validated on Glp1−/− tissue in [ 21 ]). Apoptosis was detected using an ApoAlert terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay kit according to the manufacturer's instructions (Clontech, Mountain View, CA).…”

Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders

“…In particular, circulating levels of the insulin-like growth factor-1 (IGF-1) were reported to regulate the astrocyte expression of several glutamatergic receptors and the production of eicosanoids, which ensure the optimal neurovascular coupling necessary for intense neuronal activity [113]. Furthermore, the gut microbiota, which can influence many neurological conditions (reviewed in [114]), was shown to release metabolites that tune astrocyte function directly, or through the perturbation of either microglia or meningeal natural killer cells [115][116][117][118][119]. For example, Rothhammer et al identified an anti-inflammatory effect of tryptophan metabolites, produced by Lactobacillus Reuteri and other ampicillin-sensitive gut bacteria [115], even though many aspects of this observation still need to be unraveled.…”

“…Also, calorie restriction was proposed to ameliorate the homeostatic functions of the astrocytes and to improve neuronal plasticity in the mouse hippocampus [121]. By contrast, a high fat, high sugar diet caused astrocytosis and enhanced neurotoxicity in a mouse model of spinal cord injury [119,122]. Finally, physical exercise [123][124][125] and environmental enrichment [123,126,127] importantly contributed to reduce reactive astrocytosis and alleviate the neuroinflammatory response in various animal models of injury and disease.…”

The Emerging Role of Metabolism in Brain-Heart Axis: New Challenge for the Therapy and Prevention of Alzheimer Disease. May Thioredoxin Interacting Protein (TXNIP) Play a Role?

“…As we described before, neuroinflammation affects the CAN. Western diet induces inflammation of the hypothalamus, which in turn promotes leptin resistance and weight gain [ 120 ]. Notably, depletion of the GM in mice fed with HFD results in a diminished inflammation of the hypothalamus and improves leptin sensitivity [ 120 ].…”