216-OR: O-GlcNAc Transferase in the Ventromedial Hypothalamus Regulates Lipid Metabolism through Fat Depot–Specific Sympathetic Innervation

Abstract Apolipoprotein A-IV (ApoA-IV) synthesized by the gut regulates lipid metabolism. Sympathetic innervation of adipose tissues also controls lipid metabolism. We hypothesized that ApoA-IV required sympathetic innervation to increase fatty acid (FA) uptake by adipose tissues and brown adipose tissue (BAT) thermogenesis. After 3 weeks feeding of either a standard chow diet or a high-fat diet (HFD), mice with unilateral denervation of adipose tissues received intraperitoneal administration of recombinant ApoA-IV protein and intravenous infusion of lipid mixture with radioactive triolein. In chow-fed mice, ApoA-IV administration increased FA uptake by intact BAT but not the contralateral denervated BAT or intact white adipose tissue (WAT). Immunoblots showed that, in chow-fed mice, ApoA-IV increased expression of lipoprotein lipase and tyrosine hydroxylase in both intact BAT and inguinal WAT (IWAT), while ApoA-IV enhanced protein levels of β3 adrenergic receptor, adipose triglyceride lipase, and uncoupling protein 1 in the intact BAT only. In HFD-fed mice, ApoA-IV elevated FA uptake by intact epididymal WAT (EWAT) but not intact BAT or IWAT. ApoA-IV increased sympathetic activity assessed by norepinephrine turnover (NETO) rate in BAT and EWAT of chow-fed mice, whereas it elevated NETO only in EWAT of HFD-fed mice. These observations suggest that, in chow-fed mice, ApoA-IV activates sympathetic activity of BAT and increases FA uptake by BAT via innervation, while in HFD-fed mice, ApoA-IV stimulates sympathetic activity of EWAT to shunt FAs into the EWAT.

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The autonomic nervous system regulates postprandial hepatic lipid metabolism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00614.2012 ◽

2013 ◽

Vol 304 (10) ◽

pp. E1089-E1096 ◽

Cited By ~ 24

Author(s):

Eveline Bruinstroop ◽

Susanne E. la Fleur ◽

Mariette T. Ackermans ◽

Ewout Foppen ◽

Joke Wortel ◽

...

Keyword(s):

Nervous System ◽

Autonomic Nervous System ◽

Lipid Metabolism ◽

Metabolic Regulation ◽

Sympathetic Innervation ◽

Plasma Triglyceride ◽

Fine Tuning ◽

Autonomic Nervous ◽

Glucose And Lipid Metabolism ◽

Postprandial Triglyceride

The liver is a key organ in controlling glucose and lipid metabolism during feeding and fasting. In addition to hormones and nutrients, inputs from the autonomic nervous system are also involved in fine-tuning hepatic metabolic regulation. Previously, we have shown in rats that during fasting an intact sympathetic innervation of the liver is essential to maintain the secretion of triglycerides by the liver. In the current study, we hypothesized that in the postprandial condition the parasympathetic input to the liver inhibits hepatic VLDL-TG secretion. To test our hypothesis, we determined the effect of selective surgical hepatic denervations on triglyceride metabolism after a meal in male Wistar rats. We report that postprandial plasma triglyceride concentrations were significantly elevated in parasympathetically denervated rats compared with control rats ( P = 0.008), and VLDL-TG production tended to be increased ( P = 0.066). Sympathetically denervated rats also showed a small rise in postprandial triglyceride concentrations ( P = 0.045). On the other hand, in rats fed on a six-meals-a-day schedule for several weeks, a parasympathetic denervation resulted in >70% higher plasma triglycerides during the day ( P = 0.001), whereas a sympathetic denervation had no effect. Our results show that abolishing the parasympathetic input to the liver results in increased plasma triglyceride levels during postprandial conditions.

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Biphasic brown fat temperature responses to hypothalamic stimulation in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1994.266.2.r328 ◽

1994 ◽

Vol 266 (2) ◽

pp. R328-R337 ◽

Cited By ~ 5

Author(s):

A. J. Woods ◽

M. J. Stock

Keyword(s):

Electrical Stimulation ◽

Phase 1 ◽

Sympathetic Innervation ◽

Ventromedial Hypothalamus ◽

Temperature Phase ◽

Interscapular Brown Adipose Tissue ◽

Brown Adipose ◽

Vascular Component ◽

Intracerebroventricular Injections ◽

Temperature Responses

Low-level electrical stimulation (monophasic square-wave pulses: 15 Hz, 7.0 microA, 0.5 ms) of the ventromedial hypothalamus (VMH) in anesthetized rats produced a decrease (phase 1) in interscapular brown adipose tissue (IBAT) temperature that was sustained for as long as the stimulus was applied (2-45 min). A rise in IBAT temperature (phase 2) occurred only after the stimulation had stopped. VMH stimulations ipsilateral and contralateral to a lateral hypothalamic (LH) lesion indicated that the phase 1 response required an intact LH, and denervation of IBAT showed that both phases required an intact sympathetic innervation. Central intracerebroventricular injections of amphetamine and dopamine produced decreases in IBAT temperature similar in magnitude to the phase 1 response to electrical stimulation of the VMH. This, as well as the observation that pimozide blocked phase 1, suggested that dopaminergic pathways were responsible for mediating the phase 1 decrease in IBAT temperature. The peripheral mechanisms responsible for phase 1 are unknown, but a vascular component might explain the unexpected decrease in IBAT temperature seen during sustained VMH stimulation.

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Role of ventromedial hypothalamus on sympathetic efferents of brown adipose tissue

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1984.247.4.r650 ◽

1984 ◽

Vol 247 (4) ◽

pp. R650-R654 ◽

Cited By ~ 5

Author(s):

A. Niijima ◽

F. Rohner-Jeanrenaud ◽

B. Jeanrenaud

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Spontaneous Activity ◽

Sympathetic Innervation ◽

Sympathetic Nerves ◽

Ventromedial Hypothalamus ◽

Functional Link ◽

Interscapular Brown Adipose Tissue ◽

Cold Stimulus ◽

Brown Adipose

Previous studies have suggested the presence, in hypothalamic obesity, of an impairment of the energy-dissipating capacity of brown adipose tissue ascribed to a functional disconnection of the sympathetic innervation of this tissue. The following observations demonstrate, with electrophysiological techniques, the presence of a functional link between the ventromedial hypothalamic (VMH) area and the interscapular brown adipose tissue (IBAT) in the rat: the spontaneous activity of the efferent sympathetic nerves reaching the IBAT of normal rats was increased in response to an acute cold stimulus, whereas this increase failed to occur in nerves of VMH-lesioned rats studied 4–7 days after the lesions; and the spontaneous activity of the efferent sympathetic nerves of IBAT decreased rapidly (by greater than or equal to 80% within 30 min) after acute lesions of the VMH area. It is suggested that the VMH area plays a role in increasing the activity of the efferent sympathetic nerves of IBAT during an acute cold stimulus and that alone or in relationship with other, as yet undetermined, central nervous system sites, it has a tonic stimulatory effect on the final common pathways that innervate the IBAT via the efferent sympathetic nerves.

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Hyperleptinemia: an early sign of juvenile obesity. Relations to body fat depots and insulin concentrations

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.271.3.e626 ◽

1996 ◽

Vol 271 (3) ◽

pp. E626-E630 ◽

Cited By ~ 9

Author(s):

S. Caprio ◽

W. V. Tamborlane ◽

D. Silver ◽

C. Robinson ◽

R. Leibel ◽

...

Keyword(s):

Body Fat ◽

Fat Mass ◽

Visceral Fat ◽

Subcutaneous Fat ◽

Ventromedial Hypothalamus ◽

Strong Positive Correlation ◽

Fat Depots ◽

Hyperglycemic Clamp ◽

Juvenile Obesity ◽

Fat Depot

Leptin, the OB gene product, is an adipocyte-derived circulating protein. In several rodent models of obesity, such as the db/db mice, fa/fa rats, and ventromedial hypothalamus-lesioned mice, as well as adult obese subjects, leptin mRNA expression and the circulating levels are elevated, suggesting resistance to its action. However, it is unknown whether the rise in leptin concentration occurs early in the natural evolution of human obesity or is a chronic adaptation to the obese state. Moreover, whether the distribution of body fat (i.e., visceral vs. subcutaneous abdominal fat) influences circulating leptin levels has not been assessed. We have determined in a group of obese and nonobese children and young adults whether leptin levels 1) are increased early in the development of obesity, 2) are related to a specific fat depot measured by magnetic resonance imaging, 3) vary during hyperinsulinemic, euglycemic, and hyperglycemic clamp studies, and 4) are different in males vs. females. In the basal state, leptin levels were elevated in obese children. Children and adults demonstrated a strong positive correlation between leptin concentrations and the subcutaneous fat depot (r = 0.84, P < 0.001). Surprisingly, a weaker correlation was found with visceral fat mass (r = 0.59, P = 0.001). Leptin levels remained unchanged under both euglycemic and hyperglycemic hyperinsulinemic conditions in both obese and nonobese subjects. A pronounced effect of gender on leptin levels was also observed. We conclude that, early in the development of juvenile obesity, leptin concentrations are elevated and are more closely linked to subcutaneous than visceral fat mass. Acute increases in insulin concentrations do not affect circulating leptin levels.

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