[Show abstract][Hide abstract] ABSTRACT: Insulin-independent glucose disposal (referred to as glucose effectiveness [GE]) is crucial for glucose homeostasis and, until recently, was thought to be invariable. However, GE is reduced in type 2 diabetes and markedly decreased in leptin-deficient ob/ob mice. Strategies aimed at increasing GE should therefore be capable of improving glucose tolerance in these animals. The gut-derived hormone FGF19 has previously been shown to exert potent antidiabetic effects in ob/ob mice. In ob/ob mice, we found that systemic FGF19 administration improved glucose tolerance through its action in the brain and that a single, low-dose i.c.v. injection of FGF19 dramatically improved glucose intolerance within 2 hours. Minimal model analysis of glucose and insulin data obtained during a frequently sampled i.v. glucose tolerance test showed that the antidiabetic effect of i.c.v. FGF19 was solely due to increased GE and not to changes of either insulin secretion or insulin sensitivity. The mechanism underlying this effect appears to involve increased metabolism of glucose to lactate. Together, these findings implicate the brain in the antidiabetic action of systemic FGF19 and establish the brain's capacity to rapidly, potently, and selectively increase insulin-independent glucose disposal.
The Journal of clinical investigation 10/2013; 123(11). DOI:10.1172/JCI70710 · 13.22 Impact Factor
[Show abstract][Hide abstract] 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 anti-diabetic effects since 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 (STZ-DM). This intervention completely normalized both hyperglycemia and the elevated rates of hepatic glucose production (HGP) and plasma glucagon levels, but had no effect on tissue glucose uptake in skeletal muscle or brown adipose tissue as measured using tracer dilution techniques during a basal clamp. To determine if 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 (SF1) neurons using cre-loxP technology. Our findings indicate leptin action within these neurons is not required for correction of diabetic hyperglycemia by central leptin infusion. We conclude that leptin signaling in the VMN is sufficient to mediate leptin's anti-diabetic action, but may not be necessary for this effect. Leptin action within a distributed neuronal network may mediate its effects on glucose homeostasis.
[Show abstract][Hide abstract] ABSTRACT: Astrocytes respond to multiple forms of central nervous system (CNS) injury by entering a reactive state characterized by morphological changes and a specific pattern of altered protein expression. Termed astrogliosis, this response has been shown to strongly influence the injury response and functional recovery of CNS tissues. This pattern of CNS inflammation and injury associated with astrogliosis has recently been found to occur in the energy homeostasis centers of the hypothalamus during diet-induced obesity (DIO) in rodent models, but the characterization of the astrocyte response remains incomplete. Here, we report that astrocytes in the mediobasal hypothalamus respond robustly and rapidly to purified high-fat diet (HFD) feeding by cleaving caspase-3, a protease whose cleavage is often associated with apoptosis. Although obesity develops in HFD-fed rats by day 14, caspase-3 cleavage occurs by day 3, prior to the development of obesity, suggesting the possibility that it could play a causal role in the hypothalamic neuropathology and fat gain observed in DIO. Caspase-3 cleavage is not associated with an increase in the rate of apoptosis, as determined by TUNEL staining, suggesting it plays a non-apoptotic role analogous to the response to excitotoxic neuron injury. Our results indicate that astrocytes in the mediobasal hypothalamus respond rapidly and robustly to HFD feeding, activating caspase-3 in the absence of apoptosis, a process that has the potential to influence the course of DIO.
Brain research 03/2013; 1512. DOI:10.1016/j.brainres.2013.03.033 · 2.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rodent models of obesity induced by consuming high-fat diet (HFD) are characterized by inflammation both in peripheral tissues and in hypothalamic areas critical for energy homeostasis. Here we report that unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain. Furthermore, both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding. Although these responses temporarily subsided, suggesting that neuroprotective mechanisms may initially limit the damage, with continued HFD feeding, inflammation and gliosis returned permanently to the mediobasal hypothalamus. Consistent with these data in rodents, we found evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI. These findings collectively suggest that, in both humans and rodent models, obesity is associated with neuronal injury in a brain area crucial for body weight control.
The Journal of clinical investigation 12/2011; 122(1):153-62. DOI:10.1172/JCI59660 · 13.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: By activating the Toll-like receptor 4-nuclear factor-kappaB signal transduction pathway, the bacterial endotoxin lipopolysaccharide (LPS) induces anorexia, weight loss, fever, and other components of the sickness response. By comparison, the hormones leptin and insulin cause anorexia without sickness via a central mechanism involving the phosphatidylinositol-3 kinase signaling pathway. In the current study, we investigated whether a common Toll-like receptor 4 and phosphatidylinositol-3 kinase signaling intermediate, atypical protein kinase Czeta/lambda (aPKC), contributes to changes of energy balance induced by these stimuli. Immunohistochemistry analysis revealed that aPKC is expressed in the arcuate and paraventricular nuclei of the hypothalamus, key sites of leptin, insulin, and LPS action. Although administration of LPS, insulin, and leptin each acutely increased hypothalamic aPKC activity at doses that also reduce food intake, LPS treatment caused over 10-fold greater activation of hypothalamic a PKC signaling than that induced by leptin or insulin. Intracerebroventricular pretreatment with an aPKC inhibitor blocked anorexia induced by LPS but not insulin or leptin. Similarly, LPS-induced hypothalamic inflammation (as judged by induction of proinflammatory cytokine gene expression) and neuronal activation in the paraventricular nucleus (as judged by c-fos induction) were reduced by central aPKC inhibition. Although intracerebroventricular aPKC inhibitor administration also abolished LPS-induced fever, it had no effect on sickness-related hypoactivity or weight loss. We conclude that although hypothalamic aPKC signaling is not required for food intake inhibition by insulin or leptin, it plays a key role in inflammatory anorexia and fever induced by LPS.
[Show abstract][Hide abstract] ABSTRACT: In addition to increasing insulin sensitivity and adipogenesis, peroxisome proliferator-activated receptor (PPAR)-gamma agonists cause weight gain and hyperphagia. Given the central role of the brain in the control of energy homeostasis, we sought to determine whether PPARgamma is expressed in key brain areas involved in metabolic regulation. Using immunohistochemistry, PPARgamma distribution and its colocalization with neuron-specific protein markers were investigated in rat and mouse brain sections spanning the hypothalamus, the ventral tegmental area, and the nucleus tractus solitarius. In several brain areas, nuclear PPARgamma immunoreactivity was detected in cells that costained for neuronal nuclei, a neuronal marker. In the hypothalamus, PPARgamma immunoreactivity was observed in a majority of neurons in the arcuate (including both agouti related protein and alpha-MSH containing cells) and ventromedial hypothalamic nuclei and was also present in the hypothalamic paraventricular nucleus, the lateral hypothalamic area, and tyrosine hydroxylase-containing neurons in the ventral tegmental area but was not expressed in the nucleus tractus solitarius. To validate and extend these histochemical findings, we generated mice with neuron-specific PPARgamma deletion using nestin cre-LoxP technology. Compared with littermate controls, neuron-specific PPARgamma knockout mice exhibited dramatic reductions of both hypothalamic PPARgamma mRNA levels and PPARgamma immunoreactivity but showed no differences in food intake or body weight over a 4-wk study period. We conclude that: 1) PPARgamma mRNA and protein are expressed in the hypothalamus, 2) neurons are the predominant source of PPARgamma in the central nervous system, although it is likely expressed by nonneuronal cell types as well, and 3) arcuate nucleus neurons that control energy homeostasis and glucose metabolism are among those in which PPARgamma is expressed.
[Show abstract][Hide abstract] ABSTRACT: Body weight regulation depends on neuronal signaling by adiposity-related hormones such as insulin and leptin. Activation of receptors for these hormones induces cell signaling via the insulin receptor substrate/phosphatidylinositol 3-kinase (IRS-PI3K) pathway, and growing evidence from knockout models implicates IRS-2 as a key component of this signal transduction mechanism. As a first step towards the identification of brain areas that utilize IRS-PI3K signaling in the control of energy homeostasis, we used immunohistochemical techniques to investigate the neuronal distribution of IRS-2 protein in rat brain. In the hypothalamus, strong IRS-2 staining was detected chiefly in the arcuate (ARC), ventromedial (VMN) nucleus and parvocellular paraventricular nucleus (PVN). Within the ARC, IRS-2 was co-localized with alpha melanocyte stimulating hormone (alpha-MSH) as well as neuropeptide Y (NPY). In the hindbrain, IRS-2 staining was detected in the area postrema (AP), medial nucleus of the solitary tract (mNTS), dorsal motor nucleus of the vagus nerve (DMV) and the hypoglossal nucleus (HN). Co-localization studies in the mNTS demonstrated the presence of IRS-2 in catecholamine neurons. IRS-2 protein was also found in the ventral tegmental area (VTA), an important area for reward perception, and was detected in dopamine neurons in this brain area. In summary, neurons containing IRS-2 immunoreactivity were identified in forebrain, midbrain and hindbrain areas and in cell types that are crucial for the control of food intake and autonomic function. An improved understanding of mechanisms underlying normal and abnormal energy homeostasis may be gained by analysis of the role played by signaling through IRS-2 in these brain areas.
Brain Research 10/2006; 1112(1):169-78. DOI:10.1016/j.brainres.2006.06.109 · 2.84 Impact Factor