Hyperphagia induced by hypoglycemia in rats is independent of leptin and hypothalamic neuropeptide Y (NPY)

Dryden, Simon; Pickavance, Lucy; Henderson, Lynne; Williams, Gareth

doi:10.1016/s0196-9781(98)00106-5

Cited by 21 publications

(7 citation statements)

References 39 publications

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“…In preliminary ITTs (data not shown), we determined that a dose of 0.5 U kg −1 body weight of Det was equipotent with that of 0.2 U kg −1 body weight of Glar with respect to changes in blood glucose, which is consistent with observations of others in rats. 27 Because hypoglycemia is a potent hyperphagic stimulus, 29 additional ITTs were conducted during this study in both HF- and LF-fed rats receiving Det (0.5 U kg −1 ) and Glar (0.2 U kg −1 ) to assess insulin-induced hypoglycemia (Figure 1). These doses of insulin did not induce hypoglycemia with blood glucose at 90 min in LF-fed rats (Figure 1a; Glar 5.1±0.1 mmol l −1 vs Det 5.2±0.1 mmol l −1 , P =NS) and in HF-fed rats (Figure 1b; Glar 4.7±0.1 mmol l −1 vs Det 4.7±0.1 mmol l −1 , P =NS).…”

Section: Resultsmentioning

confidence: 99%

Insulin detemir attenuates food intake, body weight gain and fat mass gain in diet-induced obese Sprague–Dawley rats

2011

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Objective:Initiation and intensification of insulin therapy commonly causes weight gain, a barrier to therapy. A contrasting body of evidence indicates that insulin functions as an adiposity negative feedback signal and reduces food intake, weight gain and adiposity via action in the central nervous system. Basal insulin analogs, detemir (Det) and glargine (Glar), have been associated with less hypoglycemia compared with neutral protamine hagedorn insulin, and Det with less weight gain, especially in patients with higher body mass index (BMI). We sought to determine whether insulin therapy per se causes body weight and fat mass gain when delivered via a clinically relevant subcutaneous (SC) route in the absence of hypoglycemia and glycosuria in non-diabetic lean and diet-induced obese rats.Materials and methods:Rats were exposed to either a low-fat diet (LFD; 13.5% fat) or high-fat diet (HFD; 60% fat), and received Det (0.5 U kg−1), Glar (0.2 U kg−1) or vehicle (Veh) SC once daily for 4 weeks. These dosages of insulin were equipotent in rats with respect to blood–glucose concentration and did not induce hypoglycemia.Results:As predicted by current models of energy homeostasis, neither insulin Det nor Glar therapy affected food intake and weight gain in LFD rats. Det treatment significantly attenuated food intake, body weight gain and fat mass gain relative to the Glar and Veh in high-fat fed animals, mirroring observations in humans.Conclusions:That neither insulin group gained excess weight, suggests weight gain with SC basal insulin therapy may not be inevitable. Our data further suggest that Det possesses a unique property to attenuate the development of obesity associated with a HFD.

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Section: Resultsmentioning

confidence: 99%

Insulin detemir attenuates food intake, body weight gain and fat mass gain in diet-induced obese Sprague–Dawley rats

2011

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“…The present finding hints at a possible influence of metformin on hunger-regulating pathways activated by hypoglycemia. As mentioned above, hypoglycemia induced hyperphagia results at least in part from an increased expression of prepro-orexin within the lateral hypothalamic areas (40,41), whereas the hypothalamic neuropeptide Y does not appear to be involved (45). However, it is not clear whether metformin after systemic administration is able to cross the blood-brain barrier to reach the hypothalamus.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Hunger by Plasma Glucose and Metformin

Schultes

Oltmanns

Kern

et al. 2003

The Journal of Clinical Endocrinology &Amp; Metabolism

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The plasma glucose concentration is a major short-term regulator of hunger and food intake. In patients with diabetes, therapies lowering plasma glucose are frequently associated with body weight gain, suggesting that lowered plasma glucose leads to increased feelings of hunger and food intake. However, as many physiological and symptomatic responses to low plasma glucose are attenuated after repeated episodes of hypoglycemia, this may also pertain to feelings of hunger. Here we tested whether the stimulatory effect of low plasma glucose on feelings of hunger is likewise reduced by repeated episodes of hypoglycemia. As metformin has been shown to reduce plasma glucose levels without increasing body weight and also to decrease food intake, we tested for possible interacting effects of this substance with hypoglycemia-induced hunger. Feelings of hunger were assessed by rating scales during 3 consecutive hypoglycemic clamps performed on 2 consecutive d in 15 normal weight men. Subjects were tested once while being treated with 850 mg metformin twice daily and once while receiving placebo. Treatment was started 14 d before the clamp experiments and was performed in a random order and double-blind fashion. Hypoglycemia markedly enhanced feelings of hunger (P < 0.001). However, rated feelings of hunger on the first and last hypoglycemic clamps were comparable (P = 0.304). Compared with placebo, metformin decreased feelings of hunger during hypoglycemia (P = 0.015). This reduction was not associated with a decrease in posthypoglycemic food intake as measured by the number of cookies consumed after the last clamp (P = 0.676). Data indicate that the stimulatory effect of low plasma glucose on hunger is not attenuated after repeated episodes of hypoglycemia, which implies that, in contrast to other symptoms, hunger is not subject to adaptive attenuation upon repeated hypoglycemia. Metformin attenuates hypoglycemia-induced hunger, but does not appear to influence posthypoglycemic food intake.

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“…An obvious candidate is NPY, the most potent appetite-stimulating peptide known, which is produced in the ARC and released in sites including the PVN and LHA (32). However, hypothalamic NPY gene expression and NPY levels were not affected by hypoglycemia in rats allowed to eat (41,42), although NPY has not been reported in fasted hypoglycemic rats. MCH, produced by a separate population of LHA neurons (32), stimulates feeding experimentally and may regulate energy homeostasis because MCH-deficient mice are hypophagic and lean (43).…”

Section: Discussionmentioning

confidence: 99%

Hypoglycemia Activates Orexin Neurons and Selectively Increases Hypothalamic Orexin-B Levels

et al. 2001

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Orexins are novel appetite-stimulating peptides expressed in the lateral hypothalamic area (LHA), and their expression is stimulated by hypoglycemia in fasted rats. We investigated activation of orexin and other neurons during insulin-induced hypoglycemia using the immediate early gene product Fos. Insulin (50 U/kg) lowered plasma glucose by >50% after 5 h and stimulated feeding sixfold compared with saline-injected controls. Hypoglycemic rats allowed to feed and normoglycemic controls both showed sparse Fos-positive (Fos + ) neurons in the LHA and the paraventricular nucleus (PVN) and arcuate nucleus (ARC) and showed none in the nucleus of the solitary tract (NTS), which relays visceral feeding signals to the LHA. In the LHA, total numbers of Fos + neurons were comparable in fed hypoglycemic and control groups (60 ± 6 vs. 52 ± 4 cells/mm 2 , P > 0.05), as were Fos + neurons immunoreactive for orexin (1.4 ± 0.4 vs. 0.6 ± 0.4 cells/mm 2 , P > 0.05). By contrast, hypoglycemic rats that were fasted showed significantly more Fos + nuclei in the LHA (96 ± 10 cells/mm 2 , P < 0.05, vs. both other groups) and Fos + orexin neurons (8.4 ± 3.3 cells/mm 2 , P < 0.001, vs. both other groups). They also showed two-to threefold more Fos + nuclei (P < 0.001) in the PVN and ARC than both fed hypoglycemic rats and controls and showed strikingly abundant Fos + neurons in the NTS and dorsal motor nucleus of the vagus. In parallel studies, whole hypothalamic orexin-A levels were not changed in hypoglycemic rats, whether fasted or freely fed, whereas orexin-B levels were 10-fold higher in hypoglycemic fasted rats than in control and hypoglycemic fed groups. These data support our hypothesis that orexin neurons are stimulated T he lateral hypothalamic area (LHA) is important in the overall regulation of feeding behavior and body weight (1). Specifically, it is crucial for the intense hunger that is caused by hypoglycemia. Eating is one component of the concerted metabolic response that is mounted to restore normal blood glucose levels. Lesions of the LHA abolish the hyperphagic response to hypoglycemia induced by insulin (2) and also to neuroglycopenia caused by 2-deoxyglucose (3).The neurochemical identities of the LHA neurons and pathways that mediate hypoglycemia-induced hyperphagia remain uncertain. The LHA contains glucose-sensitive neurons that are stimulated by hypoglycemia, and these account for ~25% of the LHA neurons (4,5). Hypoglycemia mainly activates LHA glucose-sensitive neurons indirectly (6), and pathways ascending from the brainstem are thought to be particularly important. These include a projection from the nucleus of the solitary tract (NTS) (7,8), which relays information from vagal afferents including glucoreceptors in the gut and liver (9). About 75% of recorded NTS neurons respond with altered electrical activity to blood glucose fluctuations within the physiological range (10).Recent evidence suggests that some of the LHA neurons that respond to hypoglycemia express the peptides known as orexins (11) or hypoc...

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Hyperphagia induced by hypoglycemia in rats is independent of leptin and hypothalamic neuropeptide Y (NPY)

Cited by 21 publications

References 39 publications

Insulin detemir attenuates food intake, body weight gain and fat mass gain in diet-induced obese Sprague–Dawley rats

Insulin detemir attenuates food intake, body weight gain and fat mass gain in diet-induced obese Sprague–Dawley rats

Modulation of Hunger by Plasma Glucose and Metformin

Hypoglycemia Activates Orexin Neurons and Selectively Increases Hypothalamic Orexin-B Levels

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