Hypoleptinemia, but not hypoinsulinemia, induces hyperphagia in streptozotocin‐induced diabetic rats

Hidaka, Shigekazu; Yoshimatsu, Hironobu; Kondou, Seiya; Oka, Kyoko; Tsuruta, Yoshio; Sakino, Hiroshi; Itateyama, Emi; Noguchi, Hitoshi; Himeno, Katsuro; Okamoto, Kenjirou; Teshima, Yasushi; Okeda, Toshimitsu; Sakata, Toshiie

doi:10.1046/j.1471-4159.2001.00317.x

Cited by 33 publications

(29 citation statements)

References 40 publications

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“…However, our observation that insulin and leptin have opposite effects on PI3K activity in Agrp neurons suggests that the functions of these 2 hormones as energy balance signals do not overlap completely. Indeed, differential effects of leptin and insulin on Agrp expression have been described previously in the setting of streptozotocin-induced diabetes, in which leptin, but not insulin administration, normalizes Agrp expression (28,29). Furthermore, the effects of insulin on neuronal growth and survival exceed what might be expected for a simple adiposity signal, with widespread expression of insulin receptors in many brain regions (30) and a connection between insulin action and neurodegeneration (31,32).…”

Section: Discussionmentioning

confidence: 80%

PI3K integrates the action of insulin and leptin on hypothalamic neurons

Xu¹,

Kaelin²,

Takeda³

et al. 2005

J. Clin. Invest.

289

219

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Central control of energy balance depends on the ability of proopiomelanocortin (POMC) or agouti-related protein (Agrp) hypothalamic neurons to sense and respond to changes in peripheral energy stores. Leptin and insulin have been implicated as circulating indicators of adiposity, but it is not clear how changes in their levels are perceived or integrated by individual neuronal subtypes. We developed mice in which a fluorescent reporter for PI3K activity is targeted to either Agrp or POMC neurons and used 2-photon microscopy to measure dynamic regulation of PI3K by insulin and leptin in brain slices. We show that leptin and insulin act in parallel to stimulate PI3K in POMC neurons but in opposite ways on Agrp neurons. These results suggest a new view of hypothalamic circuitry, in which the effects of leptin and insulin are integrated by anorexigenic but not by orexigenic neurons. IntroductionControl of energy homeostasis requires the central nervous system to sense and respond to changes in peripheral energy stores. Among first-order neurons suggested to date are those found in the hypothalamic arcuate nucleus that express either proopiomelanocortin (POMC) or agouti-related protein (Agrp), neuropeptides that promote negative and positive energy balance, respectively. The activity of these neurons is regulated in a reciprocal manner by leptin, an adipocyte-derived hormone that conveys afferent input from the periphery to the brain regarding the status of body energy stored in the form of fat (reviewed in refs. 1, 2, 3).The weight-reducing action of leptin involves both the inhibition of Agrp neurons (which coexpress the potent orexigen neuropeptide Y) and the stimulation of anorexigenic POMC neurons. Conversely, deficient leptin signaling in ob/ob or db/db mice activates Agrp neurons while inhibiting POMC neurons, a combination that increases food intake and reduces energy expenditure, causing profound obesity. At least 1 downstream component of leptin receptor activation involves phosphorylation of the transcription factor Stat3, and genetic manipulations that interfere with this process cause obesity (4-6), although the relative importance of Stat3 activation in different neuronal subtypes has not been addressed. Previous studies of hypothalamic circuitry and energy balance have focused on changes in membrane potential (7,8), activation of Fos (2), or modulation of synaptic plasticity (9). However, the fundamental question of how leptin activates one cell type but inhibits another remains unanswered.Here we report the development of a molecular genetics strategy that permits dynamic and cell-specific measurement of PI3K activation in hypothalamic POMC or Agrp neurons, using a brain slice

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Section: Discussionmentioning

confidence: 80%

PI3K integrates the action of insulin and leptin on hypothalamic neurons

Xu¹,

Kaelin²,

Takeda³

et al. 2005

J. Clin. Invest.

289

219

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“…In addition, mRNAs for other (an)orexogenic peptides in the hypothalamus, proopiomelanocortin (POMC), agouti-related peptide (AGRP), and galanin are altered by diabetes (14,32). It is interesting that the changes in POMCmRNA, AGRPmRNA, and body weight gain induced by diabetes were partially reversed after systemic insulin treatment, whereas NPYmRNA and CRFmRNA and food intake were totally reversed (14,33). It could well be that these peptides are more related to changes in energy expenditure or body weight than to food intake.…”

Section: Discussionmentioning

confidence: 99%

The Hepatic Vagus Mediates Fat-Induced Inhibition of Diabetic Hyperphagia

et al. 2003

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Diabetic rats both overeat high-carbohydrate diet and have altered hypothalamic neuropeptide Y (NPY) and corticotropin-releasing factor (CRF). In contrast, a high-fat diet reduces caloric intake of diabetics to normal, reflected by normal hypothalamic NPY and CRF content. How the brain senses these changes in diet is unknown. To date, no hormonal changes explain these diet-induced changes in caloric intake. We tested whether the common branch of the hepatic vagus mediates the fat signal. We presented fat in two ways. First, diabetic and vehicle-treated rats were offered a cup of lard in addition to their normal high-carbohydrate diet. Second, we switched diabetic rats from high-carbohydrate diet to high-fat diet, without choice. In streptozotocin-treated rats, both methods resulted in fat-induced inhibition of caloric intake and normalization of hypothalamic neuropeptides to nondiabetic levels. Strikingly, common branch hepatic vagotomy (unlike gastroduodenal vagotomy) entirely blocked these fat-induced changes. Although a shift in hepatic energy status did not explain the lard-induced changes in diabetic rats, the data suggested that common hepatic branch vagotomy does not interfere with hepatic energy status. Furthermore, common branch hepatic vagotomy without diabetes induced indexes of obesity. Abnormal function of the hepatic vagus, as occurs in diabetic neuropathy, may contribute to diabetic obesity. Diabetes 52: 2321-2330, 2003 I n insulin-dependent diabetes, the hormonal system of signals to the brain that ensures normal food intake is aberrant. Rats with uncontrolled streptozotocin (STZ)-induced diabetes overeat when fed a high-carbohydrate diet and display reduced body fat, high corticosterone concentrations (1), very low insulin and leptin concentrations (2-4), and impaired glucose utilization (5). Although the underlying mechanisms of diabetic hyperphagia are unknown, hypothalamic neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) are hypothesized to participate in diabetic hyperphagia (6 -9). In rats with STZ diabetes, NPY expression in the hypothalamic arcuate nucleus (Arc), associated with stimulating food intake (10,11), is increased and CRF expression in the hypothalamic paraventricular nucleus (PVN), associated with inhibiting feeding (12,13), is decreased. In addition, changes in NPY and CRF are often associated with changes in the concentrations of circulating insulin, corticosterone, and leptin, hormones known to be involved in the regulation of energy intake and expenditure through their effects on hypothalamic and brainstem neuropeptide systems (8,14). Central administration of either insulin or leptin in STZ rats decreases NPYmRNA in the PVN and reduces food intake. Furthermore, corticosterone is elevated in uncontrolled diabetes, and corticosterone administration in diabetic rats increases both Arc NPYmRNA and food intake (15) and decreases CRFmRNA (16). Taken together, these observations support the hypothesis that the effects of insulin, corticosterone, and leptin on hypotha...

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“…it is generally held that the fat burden of obesity contributes substantially to cause hyperinsulinemia [57,64,68,69,76,89,93], acute inhibition of insulin secretion by central administration of leptin has also been reported [34,62,89,102,131]. Suppression of ultradian insulin secretion from the pancreas was consistently observed when leptin expression was selectively enhanced by leptin gene transfer in the hypothalamus or in selected hypothalamic sites such as the medial preoptic area (MPOA), paraventricular hypothalamus (PVN), ventromedial hypothalamus (VMH) or ARC [4,5,17,20,22,41,42,44,109,110,133].…”

Section: A Hyperinsulinemia-althoughmentioning

confidence: 99%

“…Remarkably, this perseverance of euglycemia was evident even in the insulin-deficient streptozotocin treated diabetic mice and geneticallyinduced severely insulinopenic diabetic Akita mice [132,133,142, and unpublished]. Evidently, a distinct leptin-responsive hypothalamic mechanism orchestrates euglycemia by accelerating glucose metabolism in brown adipose tissue (BAT), liver, skeletal muscles and adipose tissue independent of insulin involvement [34,62,76,99,101,129,[131][132][133][134]136, Fig. 2].…”

Section: B Hyperglycemia and Glucosementioning

confidence: 99%

Central leptin insufficiency syndrome: An interactive etiology for obesity, metabolic and neural diseases and for designing new therapeutic interventions

Kalra

2008

Peptides

117

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This review critically reappraises recent scientific evidence concerning central leptin insufficiency versus leptin resistance formulations to explain metabolic and neural disorders resulting from subnormal or defective leptin signaling in various sites in the brain. Research at various fronts to unravel the complexities of the neurobiology of leptin is surveyed to provide a comprehensive account of the neural and metabolic effects of environmentally-imposed fluctuations in leptin availability at brain sites and the outcome of newer technology to restore leptin signaling in a sitespecific manner. The cumulative new knowledge favors a unified central leptin insufficiency syndrome over the, in vogue, central resistance hypothesis to explain the global adverse impact of deficient leptin signaling in the brain. Furthermore, the leptin insufficiency syndrome delineates a novel role of leptin in the hypothalamus in restraining rhythmic pancreatic insulin secretion while concomitantly enhancing glucose metabolism and non-shivering thermogenic energy expenditure, sequalae that would otherwise promote fat accrual to store excess energy resulting from consumption of energy-enriched diets. A concerted effort should now focus on development of newer technologies for delivery of leptin or leptin mimetics to specifically target neural pathways for remediation of diverse ailments encompassing the central leptin insufficiency syndrome.

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Hypoleptinemia, but not hypoinsulinemia, induces hyperphagia in streptozotocin‐induced diabetic rats

Cited by 33 publications

References 40 publications

PI3K integrates the action of insulin and leptin on hypothalamic neurons

PI3K integrates the action of insulin and leptin on hypothalamic neurons

The Hepatic Vagus Mediates Fat-Induced Inhibition of Diabetic Hyperphagia

Central leptin insufficiency syndrome: An interactive etiology for obesity, metabolic and neural diseases and for designing new therapeutic interventions

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