Leptin Potentiates Thermogenic Sympathetic Responses to Hypothermia

Hausberg, Martin; Morgan, Donald A.; Mitchell, Jennifer; Sivitz, William I.; Mark, Allyn L.; Haynes, William G.

doi:10.2337/diabetes.51.8.2434

Cited by 45 publications

(25 citation statements)

References 24 publications

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“…It has been demonstrated that sympathetic innervation is more abundant in BAT than in WAT [27]. Moreover, the effect of catecholamines in adipose tissues depends on the type of adrenergic receptor (AR); they have antilipolytic effect in WAT through the α 2 -ARs which inhibit adenylyl cyclase activity [28] whereas, the β 3 -ARs are abundantly expressed in BAT which activate adenylate cyclase [29].…”

Section: Discussionmentioning

confidence: 99%

Effect of Sitagliptin and Glimepiride on Glucose Homeostasis and cAMP Levels in Peripheral Tissues of HFD/STZ Diabetic Rats

Saad¹,

Kamel²,

Hanafi³

et al. 2014

AJBR

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Introduction: T2DM is a group of metabolic disorders manifested by hyperglycemia as a result of insulin insufficiency and/or resistance. The main goal of antidiabetic therapies is to lower glucose levels, and therefore prevent development of diabetes complications. DPP-4 inhibitors (e.g. sitagliptin) are relatively new antidiabetic drugs which inhibit the activity of DPP-4 enzyme and therefore prevent rapid degradation of incretin hormones. Objective: We investigated effects of sitagliptin on glucose homeostasis, lipid profile, and insulin signaling by determination of cAMP levels in peripheral tissues of HFD/STZ diabetic rats, compared to glimepiride. Methods: The experimental rats were divided into five groups, each group comprising 10 rats. Group (1) served as the normal control rats and administered DMSO (without treatments) as the vehicle. The rest of the groups were rendered diabetic by feeding HFD containing 40% fats for 4 weeks, followed by a single I.P. injection of STZ (45 mg/kg of body weight). One week after STZ injection, the rats with FBG level of ≥ 200 mg/dl were considered diabetic. Group (2) served as the diabetic untreated rats and administered DMSO (without treatments) as the vehicle. Group (3) served as diabetic rats treated with glimepiride (0.1 mg/kg of body weight). Group (4) and group (5) served as diabetic rats treated with sitagliptin (10 and 30 mg/kg of body weight, respectively). Treatments were dissolved in DMSO and were given orally for 4 weeks. At the end of the treatment period, the blood, liver and adipose tissues (White and brown) were collected for biochemical analysis. Results: In normal control rats, the highest content of cAMP was observed in BAT. Diabetic rats showed an elevation in cAMP levels of liver and WAT to be 1.3 and 3.9 fold control values, respectively, while in BAT, cAMP level decreased to be 0.4 fold control value. Sitagliptin and glimepiride significantly decreased cAMP levels in liver and WAT. Conclusion: We conclude that sitagliptin and glimepiride have comparable effects on glucose homeostasis. Both drugs have cAMP-lowering effect which may suggest their potential protecting effect against vascular complications of diabetes.

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Section: Discussionmentioning

confidence: 99%

Effect of Sitagliptin and Glimepiride on Glucose Homeostasis and cAMP Levels in Peripheral Tissues of HFD/STZ Diabetic Rats

Saad¹,

Kamel²,

Hanafi³

et al. 2014

AJBR

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“…Hence, it is often difficult to dissociate the reciprocal influence that the aforementioned parameters have on one another. Several lines of evidence suggest that leptin directly regulates energy expenditure by stimulating the activity of the sympathetic nervous system to its target tissues (94)(95)(96)(97). Although preganglionic sympathetic neurons do not express OB-Rb, leptin-sensitive neurons are found in several brain sites connected to the IML (e.g., PVH, NTS, etc.…”

Section: Body Weight Body Weight Control Is Exceptionally Complicatedmentioning

confidence: 99%

Sixteen years and counting: an update on leptin in energy balance

Gautron¹,

Elmquist²

2011

J. Clin. Invest.

311

251

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Cloned in 1994, the ob gene encodes the protein hormone leptin, which is produced and secreted by white adipose tissue. Since its discovery, leptin has been found to have profound effects on behavior, metabolic rate, endocrine axes, and glucose fluxes. Leptin deficiency in mice and humans causes morbid obesity, diabetes, and various neuroendocrine anomalies, and replacement leads to decreased food intake, normalized glucose homeostasis, and increased energy expenditure. Here, we provide an update on the most current understanding of leptin-sensitive neural pathways in terms of both anatomical organization and physiological roles. IntroductionThe nervous system regulates energy balance at the organismal level by constantly adjusting energy intake, expenditure, and storage. The influence of the nervous system over metabolic functions was first suggested at the beginning of the 20th century when excessive adiposity was associated with pituitary tumors and injury to the hypothalamus (1). However, it was not until the 1940s that selective surgical lesions of certain hypothalamic areas were found to result in extreme obesity or leanness in rats (2, 3). Over the last few decades, numerous discoveries substantially extended our understanding of the neural control of metabolism. However, it is safe to say that none were more important than the cloning of the ob gene by Friedman and colleagues in 1994 (4). The ob gene encodes the protein leptin, which is a hormone produced and secreted by the white adipose tissue, and consequently, its circulating levels are closely related to body fat mass (5, 6). Leptin deficiency in mice homozygous for a mutant ob gene (ob/ob mice) causes morbid obesity, diabetes, and various neuroendocrine anomalies, and leptin replacement leads to decreased food intake, normalized glucose homeostasis, and increased energy expenditure (7-10). Several splice variants of the leptin receptor have been identified, and the "short forms" are widely expressed in multiple tissues (11). The "long form" of the leptin receptor encodes a protein with a longer cytoplasmic domain (OB-Rb) that is highly expressed in particular sites within the CNS (refs. 10, 12, and Table 1). The short forms of the leptin receptor are also present within the CNS (11), but OB-Rb is sufficient for leptin actions on metabolism (13,14). OB-Rb is a type 1 cytokine receptor, which stimulates the JAK/STAT3 pathway (15) and PI3K (16,17). Leptin induces transcriptional changes of several genes via the JAK/STAT3 pathway, and rapid changes in cellular activity and membrane potential may underlie the acute actions of leptin (18). While actions of this hormone in peripheral tissues have been identified, studies in genetically modified mice have demonstrated that leptin action only in the CNS is sufficient to regulate body weight, feeding, energy expenditure, and glucose metabolism (13,(19)(20)(21).Since leptin is clearly not the only metabolic signal acting on the brain, the range of its effects on behavior, metabolism, and endocrinology is trul...

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“…Both TH and leptin have profound stimulatory effects on thermogenesis (Bianco & Silva 1987, Carvalho et al 1991, Silva 1995, Gong et al 1997, Hausberg et al 2002, Ukropec et al 2006. Cold exposure is associated with rapid activation of the hypothalamus-pituitary-thyroid axis (Hefco et al 1975, Joseph-Bravo et al 1998 and peripheral conversion of thyroxine (T 4 ) into tri-iodothyronine (T 3 ; Pazos- Moura et al 1991, Reed et al 1994, Lisboa et al 2003.…”

Section: Introductionmentioning

confidence: 99%

Cold exposure restores the decrease in leptin receptors (OB-Rb) caused by neonatal leptin treatment in 30-day-old rats

Dutra

Moura²,

Rodrigues³

et al. 2007

Journal of Endocrinology

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We had previously shown that neonatal leptin treatment programs thyroid function in adulthood. As both thyroid hormones (TH) and leptin increased thermogenesis, it was interesting to evaluate the effect of cold exposure on the thyroid function of neonate rats treated with leptin. Pups were divided into two groups: Lep, injected with leptin (8 mg/100 g/BW, s.c.) for the first 10 days of lactation and control (C), injected with saline. When they were 30 days old, the groups were subdivided into two subgroups: LepC and CC, which were exposed to 8 8C for 12 h and compared with C and Lep groups, maintained at 25G1 8C. Serum leptin, TH, and TSH were measured by RIA. Type I liver deiodinase (D1) and mitochondrial a-glycerol-3-phosphate dehydrogenase (mGPD) activities were assayed by the release of 125 I from 125 I-reverse and colorimetric method respectively. Leptin receptor (OB-Rb) was evaluated by western blot.Lep group had hyperleptinemia (C22%) and lower free tri-iodothyronine (FT 3 ; K33%). Cold exposure increased TH both in LepC and CC groups compared with respective controls free thyroxine (FT 4 :C63 and C39%; FT 3 :C75 and C40%). Liver D1 activity was lower in Lep (K22%) and increased with cold exposure (LepC C51% and CC C22%). The mGPD activity was lower in Lep (K34%) and increased (fourfold) when this group is cold exposed. Hypothalamic and thyroidal OB-Rb receptors were lower in Lep group (K47 and K36% respectively) and they were restored to normal levels after cold exposure. Leptin-programmed rats had higher TH response after cold exposure. OB-Rb had a fast response to cold exposure normalizing the lower levels observed in the leptin-programmed animals and may contribute to the higher TH cold responses.

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Leptin Potentiates Thermogenic Sympathetic Responses to Hypothermia

Cited by 45 publications

References 24 publications

Effect of Sitagliptin and Glimepiride on Glucose Homeostasis and cAMP Levels in Peripheral Tissues of HFD/STZ Diabetic Rats

Effect of Sitagliptin and Glimepiride on Glucose Homeostasis and cAMP Levels in Peripheral Tissues of HFD/STZ Diabetic Rats

Sixteen years and counting: an update on leptin in energy balance

Cold exposure restores the decrease in leptin receptors (OB-Rb) caused by neonatal leptin treatment in 30-day-old rats

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