Insulin signaling in LepR cells modulates fat and glucose homeostasis independent of leptin

Author(s)

Borges, Beatriz C. ^{[1, 2]} ; Han, Xingfa ^{[1, 3]} ; Allen, Susan J. ^[1] ; Garcia-Galiano, David ^[1] ; Elias, Carol F. ^{[1, 4]}

Affiliation

^[1] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 - USA

^[2] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Physiol, Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] Sichuan Agr Univ, Isotope Res Lab, Yaan - Peoples R China

^[4] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 - USA

• Document type: Journal article
• Source: AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM; v. 316, n. 1, p. E121-E134, JAN 2019.
• Web of Science Citations: 1

Abstract

Hypothalamic neurons detect changes in circulating hormones such as leptin and insulin and put forward outputs to sustain energy and glucose homeostasis. Because leptin and insulin receptors colocalize in similar to 40-60% of neurons in the hypothalamus, we characterized the metabolic phenotype of mice with selective deletion of the insulin receptor (InsR) in LepR cells. LR Delta InsR mice presented no difference in body weight and insulin levels but increased fat mass. In the light phase, LR Delta InsR mice exhibited increased food intake, locomotor activity, carbon dioxide production, and respiratory exchange rate. These mice showed reduced fat oxidation and reduced expression of cluster of differentiation 36 and AMP-activated protein kinase-alpha(1) in the liver, increased glucose oxidation in the light phase, and overall reduced basal glucose levels. To verify the impact of InsR deletion in LepR cells in obesity, we generated ob/ob InsR(fl), ob/ob LRcre, and ob/ob LR Delta InsR mice. The ob/ob LR Delta InsR mice had higher body weight, fat mass, and expression of genes related to fat metabolism in the liver. No difference in food intake despite increased neuropeptide Y and agouti-related peptide expression, and no difference in energy expenditure, fat, or glucose oxidation was found in ob/ob LR Delta InsR compared with LRcre or LR Delta InsR controls. Remarkably, basal glucose levels were reduced, and the expression of genes associated with glucose metabolism in the liver was higher. Insulin signaling in LepR cells is required for the proper fat and glucose oxidation. These effects are independent of leptin given that the leptin-deficient ob/ob LR Delta InsR mice also presented reduced glycemia and higher adiposity. The mechanisms underlying these responses remain to be unveiled. (AU)

• FAPESP's process: 16/10398-0 - Systematic screening of the transcripts and molecular and morphofunctional changes induced by metabolic dysfunctions in leptin responsive neurons in the hippocampus
• Grantee: Beatriz de Carvalho Borges Del Grande
• Support type: Scholarships in Brazil - Young Researchers
• FAPESP's process: 14/24113-1 - Systematic screening of the transcripts and molecular and morpho-functional changes induced by metabolic dysfunctions in leptin responsive neurons in the hippocampus
• Grantee: Beatriz de Carvalho Borges Del Grande
• Support type: Research Grants - Young Investigators Grants