Catecholaminergic projections into an interconnected forebrain network control the sensitivity of male rats to diet-induced obesity

Abstract

Hindbrain catecholamine neurons convey gut-derived metabolic signals to an interconnected neuronal network in the hypothalamus and adjacent forebrain. These neurons are critical for short-term glycemic control, glucocorticoid and glucoprivic feeding responses, and glucagon-like peptide 1 (GLP-1) signaling. Here we investigate whether these pathways also contribute to long-term energy homeostasis by controlling obesogenic sensitivity to a high-fat/high-sucrose choice (HFSC) diet. We ablated hindbrain-originating catecholaminergic projections by injecting anti-dopamine-β-hydroxylase-conjugated saporin (DSAP) into the paraventricular nucleus of the hypothalamus (PVH) of male rats fed a chow diet for up to 12 wk or a HFSC diet for 8 wk. We measured the effects of DSAP lesions on food choices; visceral adiposity; plasma glucose, insulin, and leptin; and indicators of long-term ACTH and corticosterone secretion. We also determined lesion effects on the number of carbohydrate or fat calories required to increase visceral fat. Finally, we examined corticotropin-releasing hormone levels in the PVH and arcuate nucleus expression of neuropeptide Y ( Npy), agouti-related peptide ( Agrp), and proopiomelanocortin ( Pomc). DSAP-injected chow-fed rats slowly increase visceral adiposity but quickly develop mild insulin resistance and elevated blood glucose. DSAP-injected HFSC-fed rats, however, dramatically increase food intake, body weight, and visceral adiposity beyond the level in control HFSC-fed rats. These changes are concomitant with 1) a reduction in the number of carbohydrate calories required to generate visceral fat, 2) abnormal Npy, Agrp, and Pomc expression, and 3) aberrant control of insulin secretion and glucocorticoid negative feedback. Long-term metabolic adaptations to high-carbohydrate diets, therefore, require intact forebrain catecholamine projections. Without them, animals cannot alter forebrain mechanisms to restrain increased visceral adiposity.

The physiological control of eating: signals, neurons, and networks

“…Similarly, although VMH glucose concentrations fall after insulin-induced hypoglycemia (432,446), direct injections of 2DG into the VMH are not followed by eating (464). These results, taken together with the fact that catecholaminergic neurons do not innervate the main body of the VMH (456,463), point to a coordinating rather than primary initiating role for the VMH in energy balance control.…”

“…This information arrives in the hypothalamus by way of a large contingent of ascending projections, most prominently from catecholaminergic neurons in the ventrolateral medulla and NTS (287,(456)(457)(458)(459)(460)(461). These projections innervate forebrain cell groups that make up a core network for integrating medulla-to-hypothalamus conveyed information (see Section V E 4) (456,458,462), including the long-term maintenance of glucose metabolism (463).…”

“…A role for dopaminergic mechanisms in these effects-possibly involving the VTA-was also strongly implicated (822), which emphasizes the involvement of ARH mechanisms in the networks associated with conveying motivation-related information to motor control networks (see Section V E 4). Second, a recent report showing that catecholaminergic projections from the NTS to ARH AgRP neurons are required for glucoprivic eating in mice (466) means that the mechanisms responsible for this particular eating behavior are most likely different from those driving deficit-induced eating and daily habitual eating, neither of which in rats, requires catecholaminergic inputs to the ARH (459,463,823).…”

Activation of catecholamine neurons in the ventral medulla reduces CCK-induced hypophagia and c-Fos activation in dorsal medullary catecholamine neurons

“…Rats in which hindbrain CA projections to the hypothalamus are retrogradely lesioned using the CA-selective immunotoxin, anti-DBH-saporin (31,56), increase visceral adiposity, insulin resistance, and blood glucose. These changes occur even when rats are maintained on a chow diet (16), but they are accentuated by high-fat diet. On the basis of the present findings, these effects may be attributable to destruction or malfunction of CA neurons in both the dorsal and ventral medulla, emphasizing the importance of CA neuron interaction, not only on emergency control of food intake, but also on the overall control of metabolic homeostasis and body weight.…”

Central Neurocircuits Regulating Food Intake in Response to Gut Inputs—Preclinical Evidence

“…Another interesting phenomenon, well documented by Levin and colleagues, has shown that HFD-fed male Sprague-Dawley rats separate into two populations, one that become hyperphagic and obese, and another that maintain their eating patterns and resist weight gain [ 133 ]. Of note, hindbrain catecholaminergic ventrolateral medulla and NTS neurons that relay GI-sensitive inputs to the PVN, DMH, and ARC within the hypothalamus are disrupted in the obesity-prone population, highlighting neurodevelopmental differences that may underlie the propensity to develop DIO [ 134 ].…”