Metformin Reduces Body Weight Gain and Improves Glucose Intolerance in High-Fat Diet-Fed C57BL/6J Mice

Abstract

In developed countries including Japan, in recent years, the incidence of obesity has sharply increased by the overintake of calorie-rich diet and exercise-lacking lifestyles. 1)Metabolic syndrome caused by obesity with abdominal adiposity especially is a strong risk factor for type 2 diabetes 2) and cardiovascular diseases.3) Obesity in humans generally involves the interaction of multiple genes and environmental factors.Pioglitazone, a thiazolidinedione that improves insulin resistance, has been widely used for the treatment of type 2 diabetes with obesity and insulin resistance. However, body weight gain is frequently observed in patients during the administration of pioglitazone. 4)On the other hand, metformin, a biguanide that improves insulin resistance similarly to pioglitazone, has been also widely used for the treatment of type 2 diabetes. It has been reported that obese patients with type 2 diabetes treated with metformin do not gain body weight; indeed many patients on this agent lose body weight by decreasing food consumption.5-8) However, the mechanisms by which metformin treatment causes reduction of food consumption and body weight loss are not fully clarified. It has been indicated that metformin increases plasma active glucagon-like peptide-1 (GLP-1) in obese nondiabetic subjects.9) GLP-1 is an incretin released from L cells in the intestine after oral ingestion of nutrients. This incretin has several actions such as stimulation of insulin biosynthesis, inhibition of glucagon secretion, and inhibition of gastric emptying in addition to promotion of satiety and inhibition of food intake. 10)Both metformin and pioglitazone are currently used as first-choice agents for the treatment for type 2 diabetes with obesity in Japan, even though they have opposite effects against body weight. Therefore it may be useful to clarify the differences in the effects of metformin and pioglitazone for prevention and treatment of obese type 2 diabetes and cardiovascular diseases produced as the result of development of metabolic syndrome. To investigate the effects of metformin on food intake and body weight gain, genetically obese diabetic mice such as db/db 11) or rats such as fa/fa, 12) GotoKakizaki (GK), 13) Otsuka Long-Evans Tokusima Fatty (OLETF), 14) and Zucker 15) have been generally used. However, daily oral administration of metformin to these genetically obese diabetic animals does not strongly affect body weight gain. On the other hand, we have recognized that daily treatment with pioglitazone given as food mixture (0.01, 0.02%) causes marked increases in food intake and body weight, although treatment with this drug removed hyperglycemia and hyperlipidemia. 16) Dietary fats are considered one of the most important environmental factors in the pathophysiology of obesity, and dietary fats-induced obesity is strongly related to lifestyle. However, it is unknown whether metformin causes body weight loss, while pioglitazone causes body weight gain, when administered to animals with high-fat diet-induced obes...

Intracerebroventricular Administration of Metformin Inhibits Ghrelin-Induced Hypothalamic AMP-Kinase Signalling and Food Intake

“…This is somewhat unexpected considering the orexigenic action of ghrelin [17,18,19,20] and the well-documented inhibitory effect of metformin on food intake [3,4,5,6,7,8,9]. Our data, however, resolve this discrepancy by demonstrating that metformin could actually block the action of ghrelin in the hypothalamus, thus presumably counteracting the stimulatory effect on circulating ghrelin levels.…”

“…The observed effect was associated with the inhibition of ghrelin-triggered activation of hypothalamic AMPK, as well as with the restoration of mTOR activity. These data suggest that the previously well-documented anorexigenic effect of metformin [3,4,5,6,7,8,9] could, at least partly, be mediated at the hypothalamic level through interference with ghrelin-induced orexigenic AMPK signalling.…”

“…Metformin has also been suggested to reduce weight in diabetic and non-diabetic patients, in contrast to sulphonylureas, thiazolidinediones and insulin, which all induce weight gain [2]. The positive effect of metformin on weight control has been associated with reduced food intake both in humans and experimental animals [3,4,5,6,7,8,9], but the mechanisms responsible for the metformin-mediated reduction of food consumption have not been fully clarified. Consistent with the ability of orally administered metformin to readily cross the blood-brain barrier [10], some recent data suggest that its anorexigenic effect might result from a direct action on the hypothalamic centres regulating satiety and feeding [11,12,13].…”

Novel mitochondrial complex I inhibitors restore glucose-handling abilities of high-fat fed mice

“…The weight gain in the mice was normalized, this was particularly evident in the epididymal fat pad (C Redondo, personal communication), which was greatly increased in the diabetic untreated animals but very similar to chow-fed controls in the compound-treated groups. The ability of these compounds to improve glucose handling in high-fat fed mice is similar to studies carried out with metformin (Matsui et al 2010) and other compounds that target complex I (Jenkins et al 2013).…”

Diabetes-Induced Prefrontal Nissl Substance Deficit and the Effects of Neem-Bitter Leaf Extract Treatment

“…Animals with fasting blood glucose 250 mg/dl or more (96 hours post-STZ induction) were included in the study. CLE was administered orally at 500 mg/kg body weight/day (500 mg/kg bw/d), while oral metformin was administered at 150 mg/kg bw/d (Matsui et al 2010). All rats were treated for eight weeks.…”