Insulin Receptor Signaling in POMC, but Not AgRP, Neurons Controls Adipose Tissue Insulin Action

Shin, Andrew C.; Filatova, Nika; Lindtner, Claudia; Chi, Tiffany; Degann, Seta; Oberlin, Douglas J.; Buettner, Christoph

doi:10.2337/db16-1238

Cited by 86 publications

(93 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, recent results unexpectedly undermine this concept, demonstrating that inhibiting Akt phosphorylation of phosphodiesterase does not eliminate this insulin action 158–160 . The mechanism of insulin action on adipocyte lipolysis thus remains a premier unsolved question in the field, and is further complicated by an indirect action of insulin on lipolysis mediated through the brain 161 . How these anti-lipolytic actions of insulin may be blunted by hyperglycemia, hyperinsulinemia or other factors under certain HFD conditions also remains a mystery 17 .…”

Section: Cellular and Molecular Causes Of Impaired Insulin Responsivementioning

confidence: 99%

Insulin action and resistance in obesity and type 2 diabetes

Czech

2017

Nat Med

954

692

View full text Add to dashboard Cite

Nutritional excess is a major forerunner of type 2 diabetes and enhances the secretion of insulin but attenuates its metabolic actions in the liver, skeletal muscle and adipose tissue. However, conflicting evidence indicates a lack of knowledge of the timing of these events during the development of obesity and diabetes and is a key gap in our understanding of metabolic disease. This Perspective reviews alternate viewpoints and recent results on the temporal and mechanistic connections between hyperinsulinemia, obesity and insulin resistance. Although much attention has addressed early steps in the insulin signaling cascade, insulin resistance in obesity appears to be largely elicited downstream of these steps. New findings also connect insulin resistance to extensive metabolic crosstalk between liver, adipose, pancreas and skeletal muscle. These and other advances over the last 5 years offer both exciting opportunities and daunting challenges in developing new therapeutic strategies for the treatment of type 2 diabetes.

show abstract

Section: Cellular and Molecular Causes Of Impaired Insulin Responsivementioning

confidence: 99%

Insulin action and resistance in obesity and type 2 diabetes

Czech

2017

Nat Med

954

692

View full text Add to dashboard Cite

show abstract

“…As effectors of hormone and circulating nutrient signaling, ARH POMC and AgRP/NPY neurons are vital contributors to energy balance control. They help control eating behavior, insulin release, energy expenditure, and carbohydrate calorie distribution (22,40,56). Because they receive and respond to catecholaminergic inputs (14,27), ARH neurons are well positioned to mediate the responses of DSAP-lesioned animals to dietary challenges.…”

Section: Dysfunction In High-fat/high-sucrose Choice Diet-fed Animalsmentioning

confidence: 99%

Catecholaminergic projections into an interconnected forebrain network control the sensitivity of male rats to diet-induced obesity

Lee

Jokiaho

Sanchez‐Watts

et al. 2018

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

Hindbrain catecholamine neurons convey gut-derived metabolic signals to an interconnected neuronal network in the hypothalamus and adjacent forebrain. These neurons are critical for short-term glycemic control, glucocorticoid and glucoprivic feeding responses, and glucagon-like peptide 1 (GLP-1) signaling. Here we investigate whether these pathways also contribute to long-term energy homeostasis by controlling obesogenic sensitivity to a high-fat/high-sucrose choice (HFSC) diet. We ablated hindbrain-originating catecholaminergic projections by injecting anti-dopamine-β-hydroxylase-conjugated saporin (DSAP) into the paraventricular nucleus of the hypothalamus (PVH) of male rats fed a chow diet for up to 12 wk or a HFSC diet for 8 wk. We measured the effects of DSAP lesions on food choices; visceral adiposity; plasma glucose, insulin, and leptin; and indicators of long-term ACTH and corticosterone secretion. We also determined lesion effects on the number of carbohydrate or fat calories required to increase visceral fat. Finally, we examined corticotropin-releasing hormone levels in the PVH and arcuate nucleus expression of neuropeptide Y ( Npy), agouti-related peptide ( Agrp), and proopiomelanocortin ( Pomc). DSAP-injected chow-fed rats slowly increase visceral adiposity but quickly develop mild insulin resistance and elevated blood glucose. DSAP-injected HFSC-fed rats, however, dramatically increase food intake, body weight, and visceral adiposity beyond the level in control HFSC-fed rats. These changes are concomitant with 1) a reduction in the number of carbohydrate calories required to generate visceral fat, 2) abnormal Npy, Agrp, and Pomc expression, and 3) aberrant control of insulin secretion and glucocorticoid negative feedback. Long-term metabolic adaptations to high-carbohydrate diets, therefore, require intact forebrain catecholamine projections. Without them, animals cannot alter forebrain mechanisms to restrain increased visceral adiposity.

show abstract

“…However, single IR or IGF1R knockout models do not completely eliminate insulin or IGF-1 signaling since both ligands can elicit signaling through the receptor that remains intact. Furthermore, up to now, most studies have focused on either the whole brain or hypothalamus (16,19,21,22). Hence, the roles of IR/IGF1R in other nuclei controlling higher neural functions, including mood and cognition, are not known.…”

mentioning

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.

160

114

View full text Add to dashboard Cite

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

show abstract

Insulin Receptor Signaling in POMC, but Not AgRP, Neurons Controls Adipose Tissue Insulin Action

Cited by 86 publications

References 49 publications

Insulin action and resistance in obesity and type 2 diabetes

Insulin action and resistance in obesity and type 2 diabetes

Catecholaminergic projections into an interconnected forebrain network control the sensitivity of male rats to diet-induced obesity

Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior

Contact Info

Product

Resources

About