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. 2014 May 22;7(4):1093-103.
doi: 10.1016/j.celrep.2014.04.010. Epub 2014 May 9.

Hypothalamic agouti-related peptide neurons and the central melanocortin system are crucial mediators of leptin's antidiabetic actions

Gabriel H M Gonçalves  1 , Wenjing Li  1 , Adriana V C-G Garcia  1 , Mariana S Figueiredo  1 , Christian Bjørbæk  2
Affiliations

Hypothalamic agouti-related peptide neurons and the central melanocortin system are crucial mediators of leptin's antidiabetic actions

Gabriel H M Gonçalves et al. Cell Rep. .

Abstract

Leptin has beneficial effects on glucose metabolism via actions in the hypothalamus, but the roles of specific subgroups of neurons responsible for these antidiabetic effects remain unresolved. We generated diabetic Lep(ob/ob) or Lepr(db/db) mice lacking or re-expressing leptin receptors (LepRb) in subgroups of neurons to explore their contributions to leptin's glucose-lowering actions. We show that agouti-related peptide (AgRP)-expressing neurons are both required and sufficient to correct hyperglycemia by leptin. LepRb in pro-opiomelanocortin (POMC) neurons or steroidogenic factor-1 (SF1) neurons are not required. Furthermore, normalization of blood glucose by leptin is blunted in Lep(ob/ob)/MC4R-null mice, but not in Lep(ob/ob) mice lacking neuropeptide Y (NPY) or gamma-aminobutyric acid (GABA) in AgRP neurons. Leptin's ability to improve glucose balance is accompanied by a reduction in circulating glucagon. We conclude that AgRP neurons play a crucial role in glucose-lowering actions by leptin and that this requires the melanocortin system, but not NPY and GABA.

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Figures

Figure 1
Figure 1. LepRbs in AgRP neurons, but not in SF1 neurons, are sufficient in mediating leptin's anti-diabetic actions
(A-E) Body weight (A), glycemia (B), food intake (9 weeks of age) (C), body composition (10-12 weeks of age) (D) and serum leptin levels (E) in HA-LepRbflox, HA-LepRbflox/Leprdb/db, HA-LepRbflox/SF1-cre/Leprdb/db, HA-LepRbflox/AgRP-ires-cre/Leprdb/db and HA-LepRbflox/Leprdb/db - PF male mice. PF, pair-fed (5-12 weeks) to lean control mice. Errors bars are shown as SEM (n = 3-8/group). Statistical analyses were done using one-way or two-way ANOVA (Bonferroni post-hoc analyses). *p < 0.05 HA-LepRbflox/AgRP-ires-cre/Leprdb/db versus HA-LepRbflox/Leprdb/db mice; **p < 0.05 HA-LepRbflox/SF1-cre/Leprdb/db or HA-LepRbflox/AgRP-ires-cre/Leprdb/db versus HA-LepRbflox/Leprdb/db mice. See also Figure S1, S2 and S3.
Figure 2
Figure 2. LepRbs in AgRP neurons, but not in SF1 or POMC neurons, are required in mediating leptin's anti-diabetic actions
(A-C) Body weight (A), glycemia (B) and food Intake (7 weeks of age) (C) in LepRbfl/fl/Lepob/ob, LepRbfl/fl/AgRP-ires-cre/Lepob/ob, LepRbfl/fl/POMC-cre/Lepob/ob and LepRbfl/fl/SF1-cre/Lepob/ob male mice. (D-F) Leptin infusion for 5 days: percent of initial body weight (D), daily food intake (E) and glycemia (F) in LepRbfl/fl/Lepob/ob - PBS (placebo group), LepRbfl/fl/Lepob/ob, LepRbfl/fl/AgRP-ires-cre/Lepob/ob, LepRbfl/fl/POMC-cre/Lepob/ob and LepRbfl/fl/SF1-cre/Lepob/ob male mice. (G) Mice were food restricted (FR) to 4 g of food/day: percent of initial body weight and glycemia in LepRbfl/fl/Lepob/ob - FR male mice. Errors bars are shown as SEM (n = 3-11/group). Statistical analyses were done using two-way ANOVA (Bonferroni post-hoc analyses). *p < 0.05 versus LepRbfl/fl/Lepob/ob mice. See also Figure S4.
Figure 3
Figure 3. Melanocortin receptors 4 (MC4Rs) are required for leptin's anti-diabetic actions
(A-D) Body weight (A), glycemia (B), food Intake (9 weeks of age) (C) and body composition (9-10 weeks of age) (D) in Lepob/ob and MC4R−/−/Lepob/ob male mice. (E-G) Leptin infusion for 12 days at 10 weeks of age: percent of initial body weight (E), daily food intake (F) and glycemia (G) in Lepob/ob and MC4R−/−/Lepob/ob male mice. Errors bars are shown as SEM (n = 3-13/group). Statistical analyses were done using Student's t test or two-way ANOVA (Bonferroni post-hoc analyses). *p < 0.05 versus Lepob/ob mice.
Figure 4
Figure 4. NPY is not required for leptin's anti-diabetic actions
(A-D) Body weight (A), glycemia (B), food Intake (9 weeks of age) (C) and body composition (9-10 weeks of age) (D) in NPY+/−/ Lepob/ob and NPY−/−/ Lepob/ob male mice. (E-G) Leptin infusion for 12 days at 10 weeks of age: percent of initial body weight (E), daily food intake (F) and glycemia (G) in NPY+/−/Lepob/ob and NPY−/−/ Lepob/ob male mice. Errors bars are shown as SEM (n = 3-7/group). Statistical analyses were done using Student's t test. *p < 0.05 versus NPY+/−/Lepob/ob mice.
Figure 5
Figure 5. GABA released by AgRP neurons is not required for leptin's anti-diabetic actions
(A-D) Body weight (A), glycemia (B), food Intake (9 weeks of age) (C) and body composition (9-10 weeks of age) (D) in Vgatfl/fl/Lepob/ob and Vgatfl/fl/AgRP-ires-cre/Lepob/ob male mice. (E-G) Leptin infusion for 12 days at 10 weeks of age: percent of initial body weight (E), daily food intake (F) and glycemia (G) in Vgatfl/fl/Lepob/ob and Vgatfl/fl/AgRP-ires-cre/Lepob/ob male mice. Errors bars are shown as SEM (n = 3-8/group).
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