1153-P: Sodium-Glucose Cotransporter-2 Inhibitors Increase Food Intake via a Mechanism That Acts on the Central Nervous System Involving Phosphorylation of Adenosine Monophosphate-Activated Protein Kinase in the Lateral Hypothalamus

IntroductionSodium glucose cotransporter-2 (SGLT2) inhibitors are widely used for diabetes treatment. Although SGLT2 inhibitors have been clinically observed to increase food intake, roles or even the presence of SGLT2 in the central nervous system (CNS) has not been established. We aimed to elucidate potential functions of SGLT2 in the CNS, and the effects of CNS-targeted SGLT2 inhibitors on food intake.Research design and methodsWe administered three kinds of SGLT2 inhibitors, tofogliflozin, dapagliflozin, and empagliflozin, into the lateral ventricle (LV) in rats and evaluated their effects on food intake. We also evaluated the effects of tofogliflozin administration in the third (3V) and fourth ventricle (4V). Intraperitoneal administration of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist known to suppress food intake, was combined with central tofogliflozin to elucidate whether GLP-1 signaling antagonizes the effect of central SGLT2 inhibitors on food intake. To elucidate potential molecular mechanisms mediating changes in feeding, hypothalamic areas associated with food intake regulation were harvested and analyzed after intracerebroventricular administration (ICV) of tofogliflozin.ResultsBolus ICV injection of tofogliflozin induced a robust increase in food intake starting at 1.5 hours postinjection, and lasting for 5 days. No effect was observed when the same dose of tofogliflozin was administered intraperitoneally. ICV dapagliflozin and empagliflozin significantly enhanced food intake, although the strength of these effects varied among drugs. Food intake was most markedly enhanced when tofogliflozin was infused into the LV. Fewer or no effects were observed with infusion into the 3V or 4V, respectively. Systemic administration of liraglutide suppressed the effect of ICV tofogliflozin on food intake. ICV tofogliflozin increased phosphorylation of AMPK and c-fos expression in the lateral hypothalamus.ConclusionsSGLT2 inhibitors in the CNS increase food intake. SGLT2 activity in the CNS may regulate food intake through AMPK phosphorylation in the lateral hypothalamic area.

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Xylazine Activates Adenosine Monophosphate-Activated Protein Kinase Pathway in the Central Nervous System of Rats

PLoS ONE ◽

10.1371/journal.pone.0153169 ◽

2016 ◽

Vol 11 (4) ◽

pp. e0153169 ◽

Cited By ~ 2

Author(s):

Xing-Xing Shi ◽

Bai-Shuang Yin ◽

Peng Yang ◽

Hao Chen ◽

Xin Li ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Protein Kinase ◽

Adenosine Monophosphate ◽

The Central Nervous System ◽

Kinase Pathway

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Role of cyclic adenosine monophosphate-dependent protein kinase (PKA) in the regulation of acetylcholine release in the central nervous system in hypertension

American Journal of Hypertension ◽

10.1016/s0895-7061(01)01840-4 ◽

2001 ◽

Vol 14 (11) ◽

pp. A213

Author(s):

K Tsuda

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Protein Kinase ◽

Acetylcholine Release ◽

Cyclic Adenosine Monophosphate ◽

Adenosine Monophosphate ◽

Dependent Protein Kinase ◽

Dependent Protein ◽

The Central Nervous System

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The regulation of food intake by insulin in the central nervous system

Journal of Neuroendocrinology ◽

10.1111/jne.12952 ◽

2021 ◽

Author(s):

Caitlin S. Mitchell ◽

Denovan P. Begg

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Food Intake ◽

The Central Nervous System

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Gastrointestinal Satiety Signals I. An overview of gastrointestinal signals that influence food intake

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00448.2003 ◽

2004 ◽

Vol 286 (1) ◽

pp. G7-G13 ◽

Cited By ~ 203

Author(s):

Stephen C. Woods

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Food Intake ◽

Social Situation ◽

Meal Size ◽

Gi Tract ◽

The Social ◽

Adiposity Signals ◽

The Central Nervous System

An overview is presented of those signals generated by the gastrointestinal (GI) tract during meals that interact with the central nervous system to create a sensation of fullness and satiety. Although dozens of enzymes, hormones, and other factors are secreted by the GI tract in response to food in the lumen, only a handful are able to influence food intake directly. Most of these cause meals to terminate and hence are called satiety signals, with CCK being the most investigated. Only one GI signal, ghrelin, that increases meal size has been identified. The administration of exogenous CCK or other satiety signals causes smaller meals to be consumed, whereas blocking the action of endogenous CCK or other satiety signals causes larger meals to be consumed. Satiety signals are relayed to the hindbrain, either indirectly via nerves such as the vagus from the GI tract or else directly via the blood. Most factors that influence how much food is eaten during individual meals act by changing the sensitivity to satiety signals. This includes adiposity signals as well as habits and learning, the social situation, and stressors.

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Interleukin-8 modulates feeding by direct action in the central nervous system

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1993.265.4.r877 ◽

1993 ◽

Vol 265 (4) ◽

pp. R877-R882 ◽

Cited By ~ 1

Author(s):

C. R. Plata-Salaman ◽

J. P. Borkoski

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Food Intake ◽

Direct Action ◽

Intraperitoneal Administration ◽

Interleukin 8 ◽

Short Term ◽

Lipopolysaccharide Endotoxin ◽

The Central Nervous System ◽

Necrosis Factor

Interleukin-8 (IL-8) is released in response to infection, inflammation, and trauma. The most important stimuli for IL-8 release during these pathological processes are IL-1, tumor necrosis factor, and bacterial lipopolysaccharide (endotoxin), factors that have been shown to suppress feeding. In the present study, the participation of IL-8 on the central regulation of feeding was investigated. Intracerebroventricular (icv) microinfusion of recombinant human IL-8 (rhIL-8, 1.0-100 ng/rat) suppressed the short-term (2-h) food intake. The most effective dose of rhIL-8, 20 ng, decreased 2-h food intake by 25% and nighttime food intake by 23%. Intracerebroventricular microinfusion of anti-rhIL-8 antibody (200 and 500 ng) blocked the effect of 20 ng rhIL-8 on 2-h and nighttime food intakes. Computerized analysis of behavioral patterns for the 2-h period demonstrated a specific reduction of meal size (by 33%), whereas meal frequency and meal duration were not affected after the icv microinfusion of 20 ng rhIL-8. This short-term food intake suppression by icv rhIL-8 was accompanied by a small, but significant, increase in cerebrospinal fluid-brain and rectal temperatures. Intraperitoneal administration of rhIL-8 in doses equivalent to those administered centrally had no effect on food intake. The results suggest that IL-8 acts directly in the central nervous system to decrease feeding. This effect of IL-8 may contribute to the food intake suppression frequently accompanying pathological processes.

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