Depleting hypothalamic somatostatinergic neurons recapitulates diabetic phenotypes in mouse brain, bone marrow, adipose and retina

Abstract

Aims/hypothesis Hypothalamic inflammation and sympathetic nervous system hyperactivity are hallmark features of the metabolic syndrome and type 2 diabetes. Hypothalamic inflammation may aggravate metabolic and immunological pathologies due to extensive sympathetic activation of peripheral tissues. Loss of somatostatinergic (SST) neurons may contribute to enhanced hypothalamic inflammation. Methods The present data show that leptin receptor-deficient (db/db) mice exhibit reduced hypothalamic SST neurons, particularly in the periventricular nucleus. We model this finding, using adeno-associated virus delivery of diphtheria toxin subunit A (DTA) driven by an SST-cre system to deplete these neurons in Sst cre/gfp mice (SST-DTA).Results SST-DTA mice exhibit enhanced hypothalamic c-Fos expression and brain inflammation as demonstrated by microglial and astrocytic activation. Bone marrow from SST-DTA mice undergoes skewed haematopoiesis, generating excess granulocytemonocyte progenitors and increased proinflammatory (C-C chemokine receptor type 2; CCR2 hi ) monocytes. SST-DTA mice exhibited a 'diabetic retinopathy-like' phenotype: reduced visual function by optokinetic response (0.4 vs 0.25 cycles/degree; SST-DTA vs control mice); delayed electroretinogram oscillatory potentials; and increased percentages of retinal monocytes. Finally, mesenteric visceral adipose tissue from SST-DTA mice was resistant to catecholamine-induced lipolysis, displaying 50% reduction in isoprenaline (isoproterenol)-induced lipolysis compared with control littermates. Importantly, hyperglycaemia was not observed in SST-DTA mice. Conclusions/interpretation The isolated reduction in hypothalamic SST neurons was able to recapitulate several hallmark features of type 2 diabetes in disease-relevant tissues.

Paracrine signaling by pancreatic δ cells determines the glycemic set point in mice

“…2018), we ruled out potentially confounding effects of hypothalamic SST neuron ablation by observing no changes in food intake between mice with and without δ cells. Our observations are consistent with a recent paper reporting that specifically ablating SST-neurons in the hypothalamus by stereotaxic injection of DTA, the catalytic unit of diphtheria toxin, had no effect on blood glucose or non-fasting insulin levels (Huang et al . 2021).…”

“…While SST-expressing neurons in the tuberal nucleus promote food intake (Luo et al 2018), we ruled out potentially confounding effects of hypothalamic SST neuron ablation by observing no changes in food intake between mice with and without δ cells. Our observations are consistent with a recent paper reporting that specifically ablating SST-neurons in the hypothalamus by stereotaxic injection of DTA, the catalytic unit of diphtheria toxin, had no effect on blood glucose or non-fasting insulin levels (Huang et al 2021). Collectively, this suggests that the consistent reductions in the glycemic set point we observe upon DT administration is not due to ablation of SST-expressing neurons.…”

Bidirectional communication between brain and visceral white adipose tissue: Its potential impact on Alzheimer's disease

“…The mesenteric vWAT in mice with the depletion of hypothalamic somatostatinergic neurons was resistant to lipolysis, as shown by a 50% reduction in isoproterenol-induced lipolysis compared to controls. 49 The hypothalamic peptide oxytocin directly inhibited the inflammation in vWAT manifested by the decreased mRNA expression of IL-6 and TNF-α, and increased concentrations of anti-inflammatory adipokines. 50 By means of an osmotic mini-pump, a long-term administration of brain-derived neurotrophic factor (BDNF) at the lateral ventricle or into the paraventricular nucleus of hypothalamus lowered food intake and body weight, decreased the weight of sWAT and vWAT (perirenal, mesenteric and epididymal depots), and reduced adipocyte size and serum concentration of triglyceride in mice.…”

“…Notably, the possible signaling pathways mediating the interaction between brain and vWAT are complex ( Figure 1 ). Specifically, we summarized the potential mechanisms or mediating factors mainly including autonomic nervous system, 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 neurotransmitters, 51 , 54 , 61 , 62 , 63 inflammation, 50 , 59 , 60 , 67 , 68 , 69 hormones, 52 , 54 , 65 , 66 fat metabolism 51 , 56 , 57 , 58 , 59 , 64 and glucose metabolism 53 , 54 , 57 on the basis of current studies.…”

Mendelian randomization study and mediation analysis about the relation of inflammatory bowel disease and diabetic retinopathy: the further exploration of gut-retina axis

“…This process also causes neurons to release fractalkine (CX3CL1), further intensifying inflammation by attracting peripheral monocytes to the hypothalamus ( 47 ). Hyperactivity of the sympathetic nervous system and hypothalamic inflammation are features of type 2 diabetes and metabolic syndrome ( 48 ). Hypothalamic inflammation and insulin resistance promote the development of DR by initiating inflammatory cascades and impairing pancreatic β-cell function and insulin production ( 49 ).…”