Differential Roles of Insulin and IGF-1 Receptors in Adipose Tissue Development and Function

Previous studies have shown that insulin and IGF-1 signaling in the brain, especially the hypothalamus, is important for regulation of systemic metabolism. Here, we develop mice in which we have specifically inactivated both insulin receptors (IRs) and IGF-1 receptors (IGF1Rs) in the hippocampus (Hippo-DKO) or central amygdala (CeA-DKO) by stereotaxic delivery of AAV-Cre into IR lox/lox /IGF1R lox/lox mice. Consequently, both Hippo-DKO and CeA-DKO mice have decreased levels of the GluA1 subunit of glutamate AMPA receptor and display increased anxiety-like behavior, impaired cognition, and metabolic abnormalities, including glucose intolerance. Hippo-DKO mice also display abnormal spatial learning and memory whereas CeA-DKO mice have impaired cold-induced thermogenesis. Thus, insulin/IGF-1 signaling has common roles in the hippocampus and central amygdala, affecting synaptic function, systemic glucose homeostasis, behavior, and cognition. In addition, in the hippocampus, insulin/IGF-1 signaling is important for spatial learning and memory whereas insulin/IGF-1 signaling in the central amygdala controls thermogenesis via regulation of neural circuits innervating interscapular brown adipose tissue.insulin | hippocampus | amygdala | metabolism | cognition

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“…functions (6,(29)(30)(31)(32). Recent studies have shown that the brain is a major target of insulin/IGF-1 signaling.…”

Section: Discussionmentioning

confidence: 99%

Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior

Soto

Cai

Konishi

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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160

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“…Furthermore, deletion of insulin receptors in UCP1 + brown/beige adipocytes also decreases BAT mass (104). Deletion of insulin receptors in adiponectin + adipocytes (white, brown, and beige adipocytes) also decreases BAT mass and impairs cold adaptive thermogenesis in mice (30). These genetic data suggest that insulin signaling is required not only for brown adipogenesis and BAT development but also for the maintenance of the thermogenic and metabolic phenotypes of BAT, and perhaps also beige fat.…”

Section: Humoral Regulation Of Brown and Beige Fat Thermogenesismentioning

confidence: 99%

Brown and Beige Adipose Tissues in Health and Disease

Rui

2017

Comprehensive Physiology

143

113

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Brown and beige adipocytes arise from distinct developmental origins. Brown adipose tissue (BAT) develops embryonically from precursors that also give to skeletal muscle. Beige fat develops postnatally and is highly inducible. Beige fat recruitment is mediated by multiple mechanisms, including de novo beige adipogenesis and white-to-brown adipocyte transdifferentiaiton. Beige precursors reside around vasculatures, and proliferate and differentiate into beige adipocytes. PDGFRα+Ebf2+ precursors are restricted to beige lineage cells, while another PDGFRα+ subset gives rise to beige adipocytes, white adipocytes, or fibrogenic cells. White adipocytes can be reprogramed and transdifferentiated into beige adipocytes. Brown and beige adipocytes display many similar properties, including multilocular lipid droplets, dense mitochondria, and expression of UCP1. UCP1-mediated thermogenesis is a hallmark of brown/beige adipocytes, albeit UCP1-independent thermogenesis also occurs. Development, maintenance, and activation of BAT/beige fat are guided by genetic and epigenetic programs. Numerous transcriptional factors and coactivators act coordinately to promote BAT/beige fat thermogenesis. Epigenetic reprograming also influences expression of brown/beige adipocyte-selective genes. BAT/beige fat is regulated by neuronal, hormonal, and immune mechanisms. Hypothalamic thermal circuits define the temperature setpoint that guides BAT/beige fat activity. Metabolic hormones, paracrine/autocrine factors, and various immune cells also play a critical role in regulating BAT/beige fat functions. BAT and beige fat defend temperature homeostasis, and regulate body weight and glucose and lipid metabolism. Obesity is associated with brown/beige fat deficiency, and reactivation of brown/beige fat provides metabolic health benefits in some patients. Pharmacological activation of BAT/beige fat may hold promise for combating metabolic diseases.

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“…However, elevated circulating insulin levels have been reported prior to the onset of obesity (3,4), and increasing evidence suggests that hyperinsulinemia is not simply an adaptive response to obesity (5). In support of this concept, adipose tissue-specific impairment of insulin signaling prevents obesity in mice (6)(7)(8)(9)(10). Furthermore, we recently reported that mice with lifelong prevention of diet-induced hyperinsulinemia by partial insulin gene deletion were protected against high-fat diet (HFD)induced obesity (11,12).…”

mentioning

confidence: 95%

Reducing insulin via conditional partial gene ablation in adults reverses diet‐induced weight gain

et al. 2018

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Excess circulating insulin is associated with obesity in humans and in animal models. However, the physiologic causality of hyperinsulinemia in adult obesity has rightfully been questioned because of the absence of clear evidence that weight loss can be induced by acutely reversing diet-induced hyperinsulinemia. Herein, we describe the consequences of inducible, partial insulin gene deletion in a mouse model in which animals have already been made obese by consuming a high-fat diet. A modest reduction in insulin production/secretion was sufficient to cause significant weight loss within 5 wk, with a specific effect on visceral adipose tissue. This result was associated with a reduction in the protein abundance of the lipodystrophy gene polymerase I and transcript release factor (Ptrf; Cavin) in gonadal adipose tissue. RNAseq analysis showed that reduced insulin and weight loss also associated with a signature of reduced innate immunity. This study demonstrates that changes in circulating insulin that are too fine to adversely affect glucose homeostasis nonetheless exert control over adiposity.—Page, M. M., Skovsø, S., Cen, H., Chiu, A. P., Dionne, D. A., Hutchinson, D. F., Lim, G. E., Szabat, M., Flibotte, S., Sinha, S., Nislow, C., Rodrigues, B., Johnson, J. D. Reducing insulin via conditional partial gene ablation in adults reverses diet-induced weight gain.

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Differential Roles of Insulin and IGF-1 Receptors in Adipose Tissue Development and Function

Cited by 118 publications

References 42 publications

Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior

Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior

Brown and Beige Adipose Tissues in Health and Disease

Reducing insulin via conditional partial gene ablation in adults reverses diet‐induced weight gain

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