Impaired Thermogenesis Research Articles

1 Insulin action, thermogenesis and obesity

The case for obesity per se being a major cause of insulin resistance has been made. There is evidence that each of the control points of insulin on glucose metabolism are negatively influenced by lipid oversupply, a characteristic of the obese state. The answer to the corollary, whether insulin resistance (a universal concomitant of obesity) can in turn lead to obesity via a decrease in thermogenesis, is more complex. Overall, the answer would appear to be no. On a population basis, obese individuals would not appear to have lower metabolic rates, whether expressed on a lean tissue or any other basis, than lean individuals. Even in the subpopulation of hypometabolic obese, there are no convincing data that the reduced metabolic rate is linked to particularly severe insulin resistance. Further, improving insulin action by weight loss would not appear to increase thermogenesis as would be predicted if insulin resistance impaired thermogenesis. A case can be made for reductions in a specific aspect of energy expenditure in obesity, that of meal-induced or glucose-induced thermogenesis, and this may be due to insulin resistance. However, meal-induced thermogenesis is a small component of total energy expenditure and total energy expenditure is not different between lean and obese. That leaves the intriguing possibility that a relative failure of prandial thermogenesis has an impact upon energy balance via impairment of satiety (related to reduced metabolic flux) and thus by increasing intake. While a potentially fruitful research avenue, too few data exist on this possibility for it to be anything more than speculative at this stage.

Thermoregulation with Age: Role of Thermogenesis and Uncoupling Protein Expression in Brown Adipose Tissue

To investigate whether attenuation of thermogenesis in interscapular brown adipose tissue (IBAT) may account for the loss of thermoregulation with age, we examined two indices of thermogenesis after two types of cold exposure: one in which the senescent rats maintained homeothermy and the other in which the senescent rats became hypothermic. To this end, we assessed body temperature, guanosine 5'-diphosphate (GDP) binding to the IBAT mitochondrial uncoupling protein (UCP) and the induction of UCP mRNA after both 1-hr and 48-hr mild cold exposures at 8 degrees C and after a more severe, 1-hr cold exposure at 4 degrees C in 3- and 24-month-old F-344 rats. Thermoneutrality was determined to occur at an ambient temperature of 26 degrees C in rats of both ages. In the 1-hr mild cold-exposed rats, there was no significant increase in GDP binding to IBAT UCP. However, after 48 hr of mild cold exposure, there was a 3-fold increase in GDP binding and a 5-fold increase in the expression of UCP mRNA despite no hypothermia in either the young or old rats. During the more severe cold exposure, the senescent rats, but not the young rats, became hypothermic. GDP binding to UCP increased 75% following cold exposure and, surprisingly was the same in young and old rats. UCP transcripts did not increase during the 1-hr cold exposure. These data, coupled with our previous findings of diminished beta 3-agonist-stimulated IBAT thermogenesis, suggest that (i) IBAT thermogenesis, at least in the senescent rats, may be mediated by other than beta 3-adrenergic receptors, and (ii) that altered heat dissipation or impaired thermogenesis at some site other than interscapular BAT is responsible for the observed hypothermia.

Recent developments in metabolism that impinge on research into the nature and treatment of diabetes mellitus.

It has been established that adenosine, its agonists, or antagonists can cause dramatic changes in insulin sensitivity in isolated soleus muscle and, moreover, can modify changes in sensitivity caused by pathophysiological conditions. Addition of adenosine deaminase to the incubation medium, which is known to lower the concentration of adenosine, increases the sensitivity of glycolysis to insulin. Addition of an adenosine-receptor agonist decreases sensitivity by about 10-fold, whereas addition of an adenosine-receptor antagonist increases sensitivity by about 10-fold. The latter totally removes the resistance of glucose utilization to insulin in the isolated soleus muscle obtained from either the genetically obese rat or from the rat fed a high sucrose diet. These findings strongly support the view that changes in insulin sensitivity in muscle can be brought about either by acute changes in the local concentration of adenosine or in the affinity or number of receptors for adenosine in muscle. However, in many of the conditions investigated, in which insulin sensitivity in muscle is changed, there was no correlation between the change in the adenosine content of the muscle and altered insulin sensitivity. It has also been shown that prostaglandin E1 can increase dramatically the sensitivity of glycolysis to insulin and that this is a specific effect of prostaglandins of the E series. It is not produced by prostacyclins, thromboxanes, or leukotrienes. It is unclear if there is a relationship between the effects of adenosine and prostaglandins. Chronic elevation of catecholamines may increase the sensitivity of glucose utilization to insulin and also increase the rate of thermogenesis by substrate cycling.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for Thyroid Hormone Deficiency in Iron-Deficient Anemic Rats

Iron-deficient anemic rats have previously been shown to have low plasma levels of thyroid hormone and a poor plasma thyroid hormone response to acute cold exposure. As an initial exploration, we examined thyroid hormone metabolism during iron deficiency in age-matched rats from three aspects: 1) plasma TSH (thyrotropin, thyroid stimulating hormone), T4 (thyroxine) and T3 (triiodothyronine) responses to graded doses of exogenous TRH (thyrotropin releasing hormone), 2) plasma T3 kinetics, and 3) rates of hepatic T3 production. Iron-deficient anemic rats had lower basal TSH values and blunted TSH responses to intravenous TRH injection at three different doses (10, 25 and 50 ng TRH/100 g body wt). Iron-deficient anemic rats also had a significant decrease in plasma T3 turnover (42 vs. 88 ng/h in controls), and significantly lower hepatic T4-5'-deiodinase activities than controls [26 vs. 44.0 ng T3/(mg protein.20 min)]. Thus, decreased rates of T3 production in iron-deficient anemic rats, as documented by turnover studies, may be related to decreased deiodinase activity and reduced peripheral formation of T3. The dampened TSH responses to TRH further facilitate or perpetuate this T3 deficiency. We propose that this abnormal thyroid state is partially responsible for impaired thermogenesis in iron-deficiency anemia.

Energy expenditure during stress ulcer formation in vulnerable rats.

Rat pups separated early from their mothers at day 15 become vulnerable to hypothermia and gastric erosion formation when food deprived and physically restrained on postnatal day 30 (S.H. Ackerman, M. A. Hofer, and H. Weiner, Science Wash. DC. 201: 373-376, 1978, and Gastroenterology 75: 649-654, 1978). We tested the hypothesis that this hypothermia is associated with a decrease in oxidative metabolism. We measured O2 consumption of 30-day-old rat pups that had been previously separated at either day 15 (15w) or day 21 (21w). When food was available, 15w rats used as much O2 as 21w rats. When rats were food deprived or food deprived and restrained, 15w rats used significantly less O2 than 21w rats, implying less heat production. We hypothesized that this decrease in heat production during food deprivation and/or restraint was due to impaired thermogenesis resulting from inadequate release of endogenous norepinephrine (NE), which is a stimulant of brown adipose tissue- (BAT) mediated thermogenesis. To test this hypothesis we administered exogenous NE to 15w to 21w rats. Exogenous NE failed to increase O2 consumption in 21w or 15w rats when injected during either food deprivation or restraint. We concluded that 30-day-old 15w rats have decreased oxidative metabolism during food deprivation and restraint and therefore become hypothermic. This decreased oxidative metabolism does not appear to be attributable to insufficient endogenous NE, since it is not reversed by the addition of exogenous NE. We suggest that a decrease in oxidative metabolism may explain susceptibility to stress ulcers in a number of previously reported experimental models.

Effet de la surrénalectomie sur la capacité de thermogenèse du tissu adipeux brun et le développement de l'obésité chez le rat Zucker fa/fa

This study was undertaken to examine whether adrenalectomy performed during the weaning period could correct some of the first metabolic abnormalities to develop in obese fa/fa rats: impaired thermogenesis in brown adipose tissue and hyperlipogenesis in interscapular brown and white (inguinal) adipose tissues. Pups were adrenalectomized or sham-operated at 23 days of age and studied at 30 days of age. Body weight, interscapular brown adipose tissue and inguinal white adipose tissue weight were decreased after adrenalectomy in Fa/fa and fa/fa pups. Adrenalectomy had no effect on the thermogenic capacity of brown adipose tissue (as assessed by GDP binding to mitochondria) which remained significantly lower in fa/fa than in Fa/fa rats. In both Fa/fa and fa/fa rats the lipogenic capacity of brown and white adipose tissues (as assessed by fatty acid synthetase activity) was dramatically reduced by adrenalectomy. However, in adrenalectomized rats, the fatty acid synthetase activity of brown and white adipose tissue remained 2 and 5-fold higher, respectively, in fa/fa than in Fa/fa rats. These results show that adrenalectomy at postweaning, did not affect specifically the rats bearing the fatty genotype but induced large alterations in both groups of rats. Adrenalectomized fa/fa animals remained obese as compared to the appropriate controls.

Control mechanisms in brown adipose tissue plasma membrane.

It is generally agreed that the site of heat production during nonshivering thermogenesis is the brown adipose tissue (BAT) and that the triggering event for heat production is the interaction of noradrenaline (NA) with its receptor on the plasma membrane. Following this initial event, several changes occur which result in increased rates of cAMP synthesis, redistribution of ions across the membrane, enhanced rates of lipolysis, and increased mitochondrial oxidation of substrates. BAT is also a target for the anabolic effect of insulin. Available evidence shows that insulin receptors are present on the BAT plasma membrane and that insulin can oppose the metabolic effects of catecholamine on BAT. We have studied more particularly the response of BAT adenylate cyclase to catecholamines in an animal model (the ob/ob mouse) which has a defective thermogenic response. The capacity of adenylate cyclase to be stimulated by catecholamines was significantly less in the tissue of obese mice than in lean controls. To produce a response equal to the half-maximal response in the lean mouse, a 10-fold increase in the NA concentration was required in the BAT of the obese mouse. These results are in harmony with those of others showing that the lipolytic response to catecholamines is abnormal in the BAT of the obese mouse. The adenylate cyclase activity can be altered by changes in the lipid composition of the diet and by manipulation of hormone levels. It is likely that the alteration in adenylate cyclase responsiveness is one of the contributing factors in the impaired thermogenesis and obesity in this animal.

Glycolytic overload and the genesis of breast cancer

It is suggested that the development of breast cancer is due to overloading of the glycolytic pathways. An excess of substrates or an excessive delivery rate of substrates to the Krebs Cycle is believed to result in the formation of acetyl CoA. Feedback mechanisms controlling the conversion of acetyl CoA to cholesterol may be overcome; the resulting high concentration of cholesterol induces the formation of pregnenolone which may then be converted into androgens, estrogens and progesterone. These steroids are in addition to those produced by gonads and adrenal glands. Glycolytic overload is also associated with an increase in fat stores which have been shown to be the site of interconversion of sex hormones. Excess sex hormones or abnormal sex hormones are believed to be the cause of breast cancer. The hypothesis presented links glycolytic overload with clinical biochemical phenomena and explains some of the anomalies observed in breast cancer experience in different ethnic groups. Changes in dietary habits during the history of man resulting in “gorging” and the consumption of highly refined sugars are possible causes of glycolytic overload. So, also, is impaired thermogenesis due to Brown Fat deficits in certain ethnic groups.

Balanced rearrangements of the autosomes: results of a longitudinal study of a newborn survey population.

Thirty-six infants were identified by cytogenetic screening at birth as having balanced rearrangements of their autosomes, and 30 of them took part in a longitudinal study of their development, together with four of their affected sibs. With the exception of one child with a de novo reciprocal translocation who died, all children attended normal schools. Congenital malformations and short stature were present in only one child who had a de novo reciprocal translocation. The IQ scores of the 10 children with de novo translocations were significantly lower than those of the 20 children with familial translocations, but there were children in the de novo group of above average intelligence. Children with familial reciprocal translocations had significantly higher IQ scores than both the Robertsonian translocations and the controls, but the numbers in each category were small and a variety of different chromosomes were involved.

A mitochondrial defect in brown adipose tissue of the obese ( [formula omitted]) mouse: Reduced binding of purine nucleotides and a failure to respond to cold by an increase in binding

Atractyloside-insensitive binding of purine nucleotides is reduced in brown adipose tissue mitochondria of the obese ( ob ob ) mouse. Exposure of the ob ob mouse to 4°C does not induce the usual increase in binding. Atractyloside-insensitive binding of purine nucleotides is believed to be a measure of the heat-producing proton conductance pathway in brown adipose tissue mitochondria. It is, therefore, suggested that the impaired thermogenesis of the ob ob mouse is due to a defect in this pathway in the mitochondria of the brown adipose tissue, the major thermogenic tissues in rodents. The greater metabolic efficiency which would result from a reduced operation of this pathway might be the basis for the obesity in the ob ob mouse.

Liver protein metabolism response to cold in genetically obese (ob/ob) mice.

THE response of obese (ob/ob) mice to the cold is reportedly impaired to the extent that they die 3–6 h after exposure. They also increase their oxygen consumption to a lesser extent than do their lean littermates in response to the cold1,2. As ob/ob mice have increased insulation due to excess body fat and respond in this way to the cold before the phenotypic expression of obesity, impaired thermogenesis seems to be a primary feature of this strain of genetic obesity. Adult obese Zucker rats also show impaired thermogenesis when exposed to cold and their mean survival time is 28 h (ref. 2). The nature and control of this thermogenesis and its possible relevance to energy balance is unclear. The involvement of protein metabolism and the energy cost of protein turnover has been postulated by3–6. Acclimatisation to the cold increases protein turnover in rats6 and in lean (Ob/+) mice (unpublished observations).

AN INTEGRATED VIEW OF THE METABOLIC AND GENETIC BASIS FOR OBESITY

The propensity to obesity in animals and man identifies those individuals who are genetically favoured to survive when food supplies are scarce. Obese subjects are limited in their ability to produce heat, either in a cold environment or after food, because of a reduced activity in skeletal muscle of a "futile" cycle in glucose metabolism. The impaired thermogenesis reduces the maintenance requirement for energy in the pre-obese individual so that a "normal" energy intake can only be balanced by excessive exercise or the expansion of adipocytes. The basal metabolic rate rises as obesity develops and compensates for the impaired thermogenic mechanism.

Impairment of cold-stimulated lipolysis by acute hypoxia.

Cold stress led to elevated plasma glycerol and free fatty acid (FFA) levels in 12 airventilated puppies. In contrast to persisting high plasma glycerol and FFA levels in the control group, marked falls of these plasma constituents occurred in six animals made hypoxic. Returning the hypoxic puppies to air breathing resulted in partial recovery of prehypoxic elevations of plasma glycerol and FFA. These observations in puppies indicate that lipolysis stimulated by cold stress was inhibited by hypoxia. Since FFA is a major fuel for heat production, reduced lipolysis at low oxygen tensions may contribute to impaired thermogenesis in young hypoxic mammals.

Inhibited Lipolysis by Hypoxia: Its Potential Role in Neonatal Thermogenesis

Because of impaired thermogenesis, cold stress is poorly tolerated by hypoxic neonates. Since free fatty acids (FFA) are a major fule for heat production, deficient FFA mobilization could contribute to reduced heat production at low oxygen tensions. In order to determine the effect of hypoxia upon cold-stimulated lipolysis and its potential role in thermogenesis, plasma glycerol and FFA levels, and deep rectal temperature were studied in cooled puppies made hypoxic. Upon lowering ambient temperature from 30 to 20°C, levels of plasma glycerol and FFA increased in 12 puppies ventilated with air (PaO2 < 75 mm Hg). In contrast to persisting high plasma glycerol and FFA levels with continued cooling in the control group, plasma glycerol fell from 172 ± 8% to 85 ± 10% and FFA from 206=25% to 105±13% mean control values (mean ± S.E.) in six animals made hypoxic (PaO2 25–35 mm Hg) for 45 min. Comparison of core temperatures during cooling revealed that the rate of temperature fall was accelerated by hypoxia, and that the mean peak fall was significantly greater in hypoxic than in control animals (p < 0.005). These observations indicate that lipolysis stimulated by cold stress is inhibited by hypoxia, which results in the reduction of FFA as a fuel source. This loss of FFA as a fuel may explain the handicap to thermogenesis observed in the hypoxic neonate.