Skip to main page content
U.S. flag
See More

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Sep;154(9):3067-76.
doi: 10.1210/en.2013-1328. Epub 2013 Jun 19.

Leptin action in the ventromedial hypothalamic nucleus is sufficient, but not necessary, to normalize diabetic hyperglycemia

Thomas H Meek  1 , Miles E Matsen, Mauricio D Dorfman, Stephan J Guyenet, Vincent Damian, Hong T Nguyen, Gerald J Taborsky Jr, Gregory J Morton
Affiliations

Leptin action in the ventromedial hypothalamic nucleus is sufficient, but not necessary, to normalize diabetic hyperglycemia

Thomas H Meek et al. Endocrinology. 2013 Sep.

Abstract

In rodent models of type 1 diabetes, leptin administration into brain ventricles normalizes blood glucose at doses that have no effect when given peripherally. The ventromedial nucleus of the hypothalamus (VMN) is a potential target for leptin's antidiabetic effects because leptin-sensitive neurons in this brain area are implicated in glucose homeostasis. To test this hypothesis, we injected leptin directly into the bilateral VMN of rats with streptozotocin-induced uncontrolled diabetes mellitus. This intervention completely normalized both hyperglycemia and the elevated rates of hepatic glucose production and plasma glucagon levels but had no effect on tissue glucose uptake in the skeletal muscle or brown adipose tissue as measured using tracer dilution techniques during a basal clamp. To determine whether VMN leptin signaling is required for leptin-mediated normalization of diabetic hyperglycemia, we studied mice in which the leptin receptor gene was deleted in VMN steroidogenic factor 1 neurons using cre-loxP technology. Our findings indicate leptin action within these neurons is not required for the correction of diabetic hyperglycemia by central leptin infusion. We conclude that leptin signaling in the VMN is sufficient to mediate leptin's antidiabetic action but may not be necessary for this effect. Leptin action within a distributed neuronal network may mediate its effects on glucose homeostasis.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Verification of cannula placement and spread of injectate after the microinjection into the VMN. A, Schematic of mediobasal hypothalamus. B, Cannula placement from a coronal section at the level of the VMN. C, A fluorescent micrograph showing cy3-labeled leptin within the VMN. D, Representative image of immunohistochemical staining of pSTAT3, a downstream marker of leptin receptor activation. For 4 animals, cy3-labeled leptin and pSTAT3 signaling overlapped with the borders of other hypothalamic areas and were excluded from the analysis. DMN, dorsomedial nucleus; 3V, third ventricle.
Figure 2.
Figure 2.
Intra-VMN leptin normalizes diabetic hyperphagia and hyperglycemia in STZ-diabetic rats. Shown are the plasma insulin (A), plasma leptin (B), mean daily food intake (C), and fed blood glucose levels (D) in STZ-induced diabetic animals receiving either vehicle (STZ-veh) and pair-fed (STZ-veh-PF) or leptin given icv (STZ-lep ICV) or directed to the VMN (STZ-lep VMN) (n = 6–9 per group). The arrow represents the start of daily leptin injections. Data represent mean ± SEM. *, P < .05 vs veh-veh; #, P < .05 vs STZ-veh-PF. The asterisk at the top of panels C and D indicates statistical differences between STZ-diabetic rats relative to veh-veh-treated controls.
Figure 3.
Figure 3.
Intra-VMN leptin suppresses HGP in STZ-diabetic rats. Three-hour fasted plasma glucose levels (A), the rate of glucose appearance (Ra) as determined from [3-3H] glucose tracer studies (B), and hepatic expression of phosphoenolpyruvate carboxykinase (Pepck) (C) and glucose 6 phosphatase (G6Pase) (D) using real-time PCR and plasma levels of glucagon (E) and ketone bodies (F) in STZ-induced diabetic animals receiving either icv vehicle and pair fed or intra-VMN leptin relative to nondiabetic controls (n = 5–8 per group) are shown. Data represent mean ± SEM. *, P < .05 vs veh-veh; #, P < .05 vs STZ-veh-PF.
Figure 4.
Figure 4.
Leptin-induced pSTAT3 activation in LepR WT and LepR KOVMN mice. pSTAT3 immunohistochemistry on brain sections from representative LepR WT mice injected with saline (A) or leptin (C) and a LepR KOVMN mouse injected with leptin (D) is shown. B, Schematic of the mediobasal hypothalamus. DMN, dorsomedial nucleus; 3V, third ventricle.
Figure 5.
Figure 5.
Antidiabetic effects of leptin do not require leptin signaling through SF1 neurons. Plasma insulin concentrations (A), blood glucose (B), food intake (C), and body weight (D) in STZ-induced diabetic animals receiving either icv vehicle or leptin relative to nondiabetic controls for both genotypes (LepR WT, and LepR KOVMN) (n = 3–7 per group) are shown. Data represent mean ± SEM. *, P < .05 vs veh-veh; #, P < .05 vs STZ-veh. The asterisk at the top of panel B indicates differences between STZ-veh- and veh-veh-treated mice for both genotypes.
See this image and copyright information in PMC

References

    1. da Silva AA, Tallam LS, Liu J, Hall JE. Chronic antidiabetic and cardiovascular actions of leptin: role of CNS and increased adrenergic activity. Am J Physiol Regul Integr Comp Physiol. 2006;291(5):R1275–R1282 - PubMed
    1. Fujikawa T, Chuang J-C, Sakata I, Ramadori G, Coppari R. Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc Natl Acad Sci USA. 2010;107(40):17391–17396 - PMC - PubMed
    1. German JP, Thaler JP, Wisse BE, et al. Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia. Endocrinology. 2011;152(2):394–404 - PMC - PubMed
    1. Hidaka S, Yoshimatsu H, Kondou S, et al. Chronic central leptin infusion restores hyperglycemia independent of food intake and insulin level in streptozotocin-induced diabetic rats. FASEB J. 2002;16(6):509–518 - PubMed
    1. Kojima S, Asakawa A, Amitani H, et al. Central leptin gene therapy, a substitute for insulin therapy to ameliorate hyperglycemia and hyperphagia, and promote survival in insulin-deficient diabetic mice. Peptides. 2009;30(5):962–966 - PubMed

Publication types

MeSH terms