LRP1 regulates food intake and energy balance in GABAergic neurons independently of leptin action

Author(s):Show less -

Kang, Min-Chel ^{[1, 2]} ; Seo, Ji A. ^{[2, 3]} ; Lee, Hyon ^{[2, 4]} ; Uner, Aykut ^[2] ; Yang, Won-Mo ^[2] ; Rodrigues, Kellen Cristina da Cruz ^[2] ; Kim, Hyun Jeong ^[2] ; Li, Wendy ^[2] ; Campbell, John N. ^[5] ; Dagon, Yossi ^[2] ; Kim, Young-Bum ^[2]

Affiliation

^[1] Korea Food Res Inst, Res Grp Food Proc, Jeollabuk Do - South Korea

^[2] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02215 - USA

^[3] Korea Univ, Dept Internal Med, Div Endocrinol, Coll Med, Seoul - South Korea

^[4] Gachon Univ, Dept Neurol, Gil Med Ctr, Incheon - South Korea

^[5] Univ Virginia, Dept Biol, Charlottesville, VA - USA

• Document type: Journal article
• Source: AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM; v. 320, n. 2, p. E379-E389, FEB 2021.
• Web of Science Citations: 0

Abstract

Low-density lipoprotein receptor-related protein 1 (LRP1) is a member of LDL receptor family that plays a key role in systemic glucose and lipid homeostasis. LRP1 also regulates energy balance in the hypothalamus by mediating leptin's anorexigenic action, although the underlying neurocircuitry involved is still unclear. Because GABAergic neurons are a major mediator of hypothalamic leptin action, we studied the role of GABAergic LRP1 in energy balance and leptin action using mice lacking LRP1 in Vgat- or AgRP-expressing neurons (Vgat-Cre; LRP1(loxP/loxP) or AgRP-Cre; LRP1(loxP/loxP)). Here, we show that LRP1 deficiency in GABAergic neurons results in severe obesity in male and female mice fed a normal-chow diet. This effect is most likely due to increased food intake and decreased energy expenditure and locomotor activity. Increased adiposity in GABAergic neuron-specific LRP1-deficient mice is accompanied by hyperleptinemia and hyperinsulinemia. Insulin resistance and glucose intolerance in these mice are occurred without change in body weight. Importantly, LRP1 in GABAergic neurons is not required for leptin action, as evidenced by normal leptin's anorexigenic action and leptin-induced hypothalamic Stat3 phosphorylation. In contrast, LRP1 deficiency in AgRP neurons has no effect on adiposity and caloric intake. In conclusion, our data identify GABAergic neurons as a key neurocircuitry that underpins LRP1-dependent regulation of systemic energy balance and body-weight homeostasis. We further find that the GABAergic LRP1 signaling pathway modulates food intake and energy expenditure independently of leptin signaling and AgRP neurons. (AU)

• FAPESP's process: 19/19938-5 - Short-term aerobic physical exercise and ApoJ action: the interorgan communications between liver and hypothalamus
• Grantee: Kellen Cristina da Cruz Rodrigues
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)