Brown adipose tissue atrophy: Effects on energy expenditure and body composition.
|Title:||Brown adipose tissue atrophy: Effects on energy expenditure and body composition.|
|Abstract:||The objective of this work was to examine the influence of brown adipose tissue (BAT) on energy expenditure and body composition. Insights were gained from rodent models with BAT disruption, which is expected to contribute to obesity due to a deficit in energy expenditure for thermogenesis (Himms-Hagen 1989b). The capsaicin-desensitized (Cap-Des) rat has atrophied BAT with impaired thermogenesis, contradictorily leading to a decrease in body fat. Indeed, aging-associated obesity and hyperplasia of retroperitoneal white adipose tissue was prevented in 13.5 month old Cap-Des rats. The loss of function of Cap-sensitive afferent autonomic nerves (destroyed in Cap-Des rats) results in an alteration in energy balance conducive to leanness. It was suggested that the attenuated aging-associated increase in circulating calcitonin gene-related peptide (derived mainly from Cap-sensitive nerves) in the Cap-Des rat results in a lower degree of aging-associated insulin-resistance, hence in a lesser degree of obesity. Rats with a lesion in the nucleus of the solitary tract (NTS) are known to have an impaired capacity to increase their oxygen uptake and the temperature of their interscapular (I) BAT after administration of catecholamines. A similar impairment was seen in the Cap-Des rat, known also to sustain a lesion in the NTS, and associated with marked atrophy of IBAT. The disruption of the NTS did not cause BAT atrophy by the parameters measured; atrophy of BAT in Cap-Des rats is not due to the NTS-lesion that they sustain. UCP-DTA transgenic mice have a partial ablation of BAT, accomplished by linking DTA (diphtheria toxin A chain) to the uncoupling protein1 (UCP1) promoter. UCP1-expressing brown adipocytes are destroyed in the UCP-DTA transgenic mouse when the tissue is stimulated. As expected, these mice develop massive obesity; also present are hyperphagia, insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia characteristic of noninsulin-dependent diabetes mellitus (Lowell et al. 1993). UCP-DTA and control mice were raised at thermoneutrality (35$\sp\circ$C) in order to suppress BAT thermogenesis. As predicted, eliminating the deficit in BAT thermogenesis present in the UCP-DTA mice corrected their obesity and hyperphagia. UCP is not totally eliminated in the UCP-DTA mice, as measured by an antibody that detects UCP1, UCP2 (and probably UCP3), and these mice are not sensitive to cold (Lowell et al. 1993). Mice were acclimated to mild cold (14$\sp\circ$C) to determine the nature of compensation for the lack of UCP1-expressing brown adipocytes in UCP-DTA mice. BAT does grow in cold-adapted UCP-DTA mice, perhaps by substitution of brown adipocytes expressing a different UCP isoform for brown adipocytes that would normally express UCP1. Adjustment of food intake in accordance with environmental temperature was shown to occur independent of changes in serum leptin concentration. Intact BAT was shown to be necessary for the control of food intake at temperatures below thermoneutrality. Because the lack of UCP1-mediated thermogenesis in BAT of knockout mice is known not to induce hyperphagia, we propose the deficiency of UCP1-expressing brown adipocytes, specifically the absence of a postulated satiety factor normally secreted from them, is responsible for the hyperphagia of the UCP-DTA mice at 24$\sp\circ$C.|
|Collection||Thèses, 1910 - 2010 // Theses, 1910 - 2010|